Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical

ABSTRACT

Methods and compositions are provided for treating neuropsychiatric disorders such as schizophrenia, depression, attention deficit disorder, mild cognitive impairment, dementia, and bipolar disorder. The methods entail administering to a patient diagnosed as having a neuropsychiatric disorder (e.g., schizophrenia, depression, attention deficit disorder, mild cognitive impairment, dementia bipolar disorder, etc.) or as at risk for a neuropsychiatric disorder a benzoic acid, benzoic acid salt, and/or benzoic acid derivative, and/or a sorbic acid, sorbic acid salt, and/or sorbic acid derivative, in combination with a neuropharmacological agent (e.g., an antipsychotic, an antidepressant, medications for attention deficit and hyperactivity disorder, cognitive impairment, or dementia, etc.) where the benzoic acid, benzoic acid salt, or benzoic acid derivative, and/or a sorbic acid, sorbic acid salt, and/or sorbic acid derivative, is in an amount sufficient to increase the efficacy of the neuropharmacological agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.14/552,298, filed on Nov. 24, 2014, now U.S. Pat. No. 9,675,604, whichis a division of U.S. patent application Ser. No. 12/689,957, filed onJan. 19, 2010, now U.S. Pat. No. 9,649,304, which claims the benefit ofand priority to U.S. Provisional Patent Application Ser. No. 61/145,931,filed on Jan. 20, 2009, the disclosures of each of which areincorporated by reference herein in their entirety for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

[Not Applicable]

FIELD OF THE INVENTION

This is invention pertains the field of neuropsychiatry. In particulartreatment methods are provided for neuropsychiatric disorders.

BACKGROUND OF THE INVENTION

Schizophrenia, Alzheimer's Disease, autism, depression, benignforgetfulness, childhood learning disorders, close head injury, andattention deficit disorder (ADD), dementia, mild cognitive impairment,ataxia, spinocerebellar degeneration, Parkinson's disease, obsessivecompulsive disorder (OCD), substance abuse, and substance dependence areexamples of neuropsychiatric disorders. Autism, for example, is adevelopmental mental disorder characterized by autistic behavior, socialfailure, and language delay. Alzheimer's Disease is a form of dementiathat typically involves progressive mental deterioration, manifested bymemory loss, confusion, and disorientation. Alzheimer's Diseasetypically is treated by acetylcholine esterase inhibitors such astacrine hydrochloride or donepezil. Attention Deficit Disorder is adisorder that is most prevalent in children and is associated withincreased motor activity and a decreased attention span. AttentionDeficit Disorder commonly is treated by administration ofpsychostimulants or other medications such as Ritalin, Dexedrin, oratomoxetin. Depression is a clinical syndrome that includes a persistentsad mood or loss of interest in activities, which persists for at leasttwo weeks in the absence of treatment. Conventional therapeutics includeserotonin uptake inhibitors (e.g., PROZAC®), monoamine oxidaseinhibitors, and tricyclic antidepressants.

The term schizophrenia represents a group of neuropsychiatric disorderscharacterized by dysfunctions of the thinking process, such asdelusions, hallucinations, and extensive withdrawal of the patient'sinterests from other people. Approximately one percent of the worldwidepopulation is afflicted with schizophrenia, and this disorder isaccompanied by high morbidity and mortality rates.

Conventional antipsychotic drugs, which act on the dopamine D₂,receptor, can be used to treat the positive symptoms of schizophrenia,such as delusion and hallucination. In general, conventionalantipsychotic drugs and the new atypical antipsychotic drugs, which acton the dopamine D₂, and 5HT2 serotonin receptor, are limited in theirability to treat cognitive deficits and negative symptoms such as affectblunting (i.e., lack of facial expressions), anergia, and socialwithdrawal.

SUMMARY OF THE INVENTION

In certain embodiments this invention pertains to “combination”pharmaceutical compositions comprising a benzoic acid, benzoic acidsalt, benzoic acid ester or other benzoic acid derivative, and/or asorbic acid, sorbic acid salt, sorbic acid ester, or other sorbic acidderivative and a neuropharmaceutical (e.g., an antipsychotic drug (e.g.,risperidone, olanzapine, etc.), and antidepressant (e.g., sertraline,fluoxetine hydrochloride, etc.), a psychotropic medication for attentiondeficit and hyperactivity disorder (e.g., Ritalin, Dexedrine,Atomoxetine, etc.), a psychotropic medication for dementia (e.g.,Aricept, memantine), and the like). Typically, the benzoic acid, benzoicacid salt, benzoic acid ester or other benzoic acid derivative, and/or asorbic acid, sorbic acid salt, sorbic acid ester, or other sorbic acidderivative is present in an amount sufficient to increase the efficacyof the neuropharmaceutical. In certain embodiments the benzoic acid isprovided as a benzoic acid salt (e.g. sodium benzoate, potassiumbenzoate, calcium benzoate, etc.). In certain embodiments the benzoicacid, benzoic acid salt, or derivative thereof is selected from thegroup consisting of benzoic acid, sodium benzoate, potassium benzoate,calcium benzoate, 2-aminobenzoate, 3-aminobenzoate, and 4-aminobenzoate.In certain embodiments the sorbic acid is provided as a sorbic acid salt(e.g., sodium sorbate, potassium sorbate, calcium sorbate, etc.). Incertain embodiments the sorbic acid, sorbic acid salt, sorbic acidester, and/or sorbic acid derivative is selected from the groupconsisting of sorbic acid, sodium sorbate, potassium sorbate, calciumsorbate, sorbohydroxamic acid, a sorbic aldehyde, a sorbic acid-thioladduct, 8-quinolinylsorbate, and m-nitrosorbanilide.

In certain embodiments the ratio of benzoic acid, benzoic acid salt, orbenzoic acid derivative and/or sorbic acid, sorbic acid salt, or sorbicacid derivative to neuropharmaceutical is stoichiometrically greaterthan 2:1, greater than 3:1, greater than 4:1 greater than 5:1, greaterthan 6:1, greater than 7:1, greater than 8:1, greater than 9:1, orgreater than 10:1 or 20:1.

In certain embodiments the neuropharmaceutical is selected from thegroup consisting of an antidepressant, an antipsychotic, aphsychostimulant, a mood stablizer, an anxiolytic, an ADHD therapeutic,and an Alzheimer's disease therapeutic. In certain embodiments theneuropharmaceutical is an antipsychotic drug (e.g., butyrophenone,phenothiazine, fluphenazine, perphenazine, prochlorperazine,thioridazine, trifluoperazine, mesoridazine, promazine, triflupromazine,levomepromazine, promethazine, thioxanthene, chlorprothixene,flupenthixol, thiothixene, zuclopenthixol, clozapine, olanzapine,risperidone, quetiapine, ziprasidone, amisulpride, asenapine,paliperidone, aripiprazole, a dopamine partial agonist, lamotrigine,memantine, tetrabenazine, cannabidiol, and/or LY2140023). In certainembodiments the neuropharmaceutical is an antidepressant drug (e.g., amonoamine oxidase inhibitor (MAOI), a tricyclic antidepressant (TCA), atetracyclic antidepressant (TeCA), a selective serotonin reuptakeinhibitor (SSRI), and a serotonin-norepinephrine reuptake inhibitor(SNRI). In certain embodiments the neuropharmaceutical is an ADHDmedication (e.g., Ritalin, Dexedrine, Atomoxetine, and the like). Incertain embodiments the neuropharmaceutical is a medication forimproving cognition and/or inhibiting neurodegeneration (e.g., Aricept.memantine, etc.).

Also provided are methods for mitigating one or more symptoms of aneuropsychiatric disorder (e.g., schizophrenia, depression, attentiondeficit disorder, mild cognitive impairment, dementia, attention deficithyperactivity disorder (ADHD), bipolar disorder, and the like). Themethods typically involve administering to a subject in need thereof abenzoic acid, benzoic acid salt, or benzoic acid derivative and/or asorbic acid, sorbic acid salt, or sorbic acid derivative in an amountsufficient to mitigate one or more symptoms of a neuropsychiatricdisorder. In certain embodiments the method comprises administering tothe subject the benzoic acid, benzoic acid salt, or benzoic acidderivative and/or a sorbic acid, sorbic acid salt, or sorbic acidderivative in conjunction with a neuropharmaceutical, where the benzoicacid, benzoic acid salt, or benzoic acid derivative and/or a sorbicacid, sorbic acid salt, or sorbic acid derivative is administered in anamount sufficient to increase the efficacy of the neuropharmaceutical.In certain embodiments the benzoic acid, benzoic acid salt, benzoic acidester, or derivative thereof and/or a sorbic acid, sorbic acid salt,sorbic acid ester, or derivative thereof and the neuropharmaceutical areadministered simultaneously (i.e., separately or in a combinedformulation). In certain embodiments the benzoic acid, benzoic acidsalt, benzoic acid ester, or derivative thereof and/or a sorbic acid,sorbic acid salt, sorbic acid ester, or derivative thereof isadministered before or after the neuropharmaceutical.

In certain embodiments of the methods, the benzoic acid is provided as abenzoic acid salt (e.g. sodium benzoate, potassium benzoate, calciumbenzoate, etc.). In certain embodiments the benzoic acid, benzoic acidsalt, or derivative thereof is selected from the group consisting ofbenzoic acid, sodium benzoate, potassium benzoate, calcium benzoate,2-aminobenzoate, 3-aminobenzoate, and 4-aminobenzoate. In certainembodiments the sorbic acid is provided as a sorbic acid salt (e.g.,sodium sorbate, potassium sorbate, calcium sorbate, etc.). In certainembodiments the sorbic acid, sorbic acid salt, sorbic acid ester, and/orsorbic acid derivative is selected from the group consisting of sorbicacid, sodium sorbate, potassium sorbate, calcium sorbate,sorbohydroxamic acid, a sorbic aldehyde, a sorbic acid-thiol adduct,8-quinolinylsorbate, and m-nitrosorbanilide.

In certain embodiments of the methods, the ratio of benzoic acid,benzoic acid salt, or benzoic acid derivative and/or sorbic acid, sorbicacid salt, or sorbic acid derivative to neuropharmaceutical isstoichiometrically greater than 2:1, greater than 3:1, greater than 4:1greater than 5:1, greater than 6:1, greater than 7:1, greater than 8:1,greater than 9:1, or greater than 10:1 or 20:1.

In certain embodiments of the methods, the neuropharmaceutical isselected from the group consisting of an antidepressant, anantipsychotic, a psychostimulant, a mood stablizer, an anxiolytic, anADHD therapeutic, and an Alzheimer's disease therapeutic. In certainembodiments the, the neuropsychiatric disorder is schizophrenia and/orbipolar disorder, and the neuropharmaceutical is an antipsychotic drug(e.g., butyrophenone, phenothiazine, fluphenazine, perphenazine,prochlorperazine, thioridazine, trifluoperazine, mesoridazine,promazine, triflupromazine, levomepromazine, promethazine, thioxanthene,chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, clozapine,olanzapine, risperidone, quetiapine, ziprasidone, amisulpride,asenapine, paliperidone, aripiprazole, a dopamine partial agonist,lamotrigine, memantine, tetrabenazine, cannabidiol, and/or LY2140023).In certain embodiments the, the neuropsychiatric disorder is depression,and the neuropharmaceutical is an antidepressant drug (e.g., a monoamineoxidase inhibitor (MAOI), a tricyclic antidepressant (TCA), atetracyclic antidepressant (TeCA), a selective serotonin reuptakeinhibitor (SSRI), and a serotonin-norepinephrine reuptake inhibitor(SNRI). In certain embodiments, the neuropsychiatric disorder is ADHDand the neuropharmaceutical is an ADHD medication (e.g., ritalin,dexedrine, atomoxetine, and the like). In certain embodiments, theneuropsychiatric disorder is characterized by loss in cognition and/orneurodegeneration (e.g. Alzheimer's disease), and theneuropharmaceutical is a medication for improving cognition and/orinhibiting neurodegeneration (e.g., Aricept. memantine, etc.). Invarious embodiments of the methods, the subject is a human diagnosedhaving or as at risk for a neuropsychiatric disorder. In variousembodiments the subject is a non-human mammal (e.g., a canine, a feline,an equine, etc.). In various embodiments the methods are performedprophylactically, or therapeutically.

Uses for benzoic acid, benzoic acid salt, or benzoic acid derivativeand/or a sorbic acid, sorbic acid salt, or sorbic acid derivative asactive agents in the manufacture of medicaments for the treatment of aneuropsychiatric disorder are provided where the benzoic acid, benzoicacid salt, benzoic acid ester, or benzoic acid derivative and/or asorbic acid, sorbic acid salt, sorbic acid ester or sorbic acidderivative is present in an amount effective to mitigate one or moresymptoms of the neuropsychiatric disorder are also provided. Similarly,uses for benzoic acid, benzoic acid salt, or benzoic acid derivativeand/or a sorbic acid, sorbic acid salt, or sorbic acid derivative incombination with a neuropharmaceutical in the manufacture of amedicament for the treatment of a neuropsychiatric disorder, where thebenzoic acid, benzoic acid salt, or benzoic acid derivative and/or asorbic acid, sorbic acid salt, or sorbic acid derivative is present inan amount sufficient to increase the efficacy of the neuropharmaceuticalare provided. In various embodiments the benzoic acid, benzoic acidsalt, benzoic acid ester, and/or benzoic acid derivative is a benzoicacid salt. In various embodiments the benzoic acid, benzoic acid salt,benzoic acid ester, and/or benzoic acid derivative is selected from thegroup consisting of benzoic acid, sodium benzoate, potassium benzoate,calcium benzoate, 2-aminobenzoate, 3-aminobenzoate, and 4-aminobenzoate.In various embodiments the sorbic acid, sorbic acid salt, sorbic acidester, and/or sorbic acid derivative is a sorbic acid salt. In certainembodiments the sorbic acid, sorbic acid salt, sorbic acid ester, and/orsorbic acid derivative is selected from the group consisting of sorbicacid, sodium sorbate, potassium sorbate, calcium sorbate,sorbohydroxamic acid, a sorbic aldehyde, a sorbic acid-thiol adduct,8-quinolinylsorbate, and m-nitrosorbanilide. In various embodiments theneuropharmaceutical, when present, includes any one or more of theneuropharmaceuticals described herein.

In certain embodiments this invention pertains to the discovery thatadministration of any two or all three of (i) an NMDA(N-methyl-D-aspartate)-Enhancer, and/or (ii) a glycine transporterinhibitor, and/or (iii) a D-amino Acid Oxidase Inhibitor (DAAOI) to asubject having or at high risk for a neuropsychiatric disorder, providessubstantially greater efficacy at reducing or eliminating symptoms ofthe disorder than previously known single-agent therapeutic regimes. Invarious embodiments, this invention also provides pharmacologicalcompositions comprising any two or all three agents in combination andmethods utilizing such combined formulations.

Accordingly in certain embodiments, a pharmaceutical composition (andmethod of use thereof) is provided where the composition comprises aD-amino Acid Oxidase Inhibitor (DAAOI) (e.g., benzoic acid, benzoic acidsalt, or benzoic acid derivative and/or a sorbic acid, sorbic acid salt,or sorbic acid derivative) and/or an NMDA enhancer and/or a glycinetransporter inhibitor. In certain embodiments, a pharmaceuticalcomposition is provided where the composition comprises a benzoic acid,benzoic acid salt, or benzoic acid derivative and/or a sorbic acid,sorbic acid salt, or sorbic acid derivative; and an NMDA enhancer. Incertain embodiments, a pharmaceutical composition is provided where thecomposition comprises a benzoic acid, benzoic acid salt, or benzoic acidderivative and/or a sorbic acid, sorbic acid salt, or sorbic acidderivative; and a glycine transporter inhibitor. In certain embodiments,a pharmaceutical composition is provided where the composition comprisesa benzoic acid, benzoic acid salt, or benzoic acid derivative and/or asorbic acid, sorbic acid salt, or sorbic acid derivative; an NMDAenhancer; and a glycine transporter inhibitor. In various embodiments ofthese compositions, the D-amino Acid Oxidase Inhibitor comprises benzoicacid, benzoic acid salt, or benzoic acid derivative and/or a sorbicacid, sorbic acid salt, or sorbic acid derivative alone together witheach other, or alone or together with each other and an additional DAAOinhibitor described herein. In various embodiments the NMDA enhancer,when present, comprises one or more NMDA enhancers described herein. Invarious embodiments the glycine transporter inhibitor, when presentcomprises one or more glycine transporter inhibitors described herein.

In various embodiments these compositions comprise an additionalneuropharmaceutical, e.g., an antipsychotic, an antidepressant, apsychostimulant, a mood stabilizer, an anxiolytic, an Alzheimer'sdisease therapeutic, and/or other psychotropic. In certain embodimentsthe additional therapeutic agent is one or more agents selected from theneuropharmaceuticals described herein (e.g., diazepam, bromazepam,prazepam, chlordiazepoxide, clobazam, estazolam, flurazepam, clonazepam,temazepam, triazolam, alprazolam, midazolam, brotizolam, nitrazepam,flunitrazepam, oxazepam, quazepam, lorazepam, temazepam, triazolam,zolpidem, zopiclone, zaleplon, chlorpromazine, thioridazine,mesoridazine, fluphenazine, perphenazine, trifluoperazine, thiothixene,haloperidol, loxapine, molindone, clozapine, risperidone, olanzapine,quetiapine, haloperidol decanoate, fluphenazine decanoate, fluphenazineenanthate, risperdal consta, sulpiride, ziprasidone, aripiprazole,paliperidone, acetophenazine, chlorprothixene, droperidol, pimozide,butaperazine, carphenazine, remoxipride, piperacetazine, amitriptyline,imipramine, nortriptiline, protriptyline, desipramine, trimipramine,amoxapine, bupropion, bupropion sr, citalopram, s-citalopram,clomipramine, desipramine, doxepin, duloxetine, milnacipran, fluoxetine,fluvoxamine, imipramine, isocarboxazid, isoniazid, iproniazid,fluoxetine, paroxetine, sertraline fluvoxamine, venlafaxine, velafaxinexr, milnacipram and duloxetine, mirtazapine, mianserin, reboxetine,selegiline, tranylcypromine, trazodone, nefazodone, phenelzine,lamatrogine, lithium, topiramate, gabapentin, carbamazepine,oxacarbazepine, valporate, maprotiline, mirtazapine, brofaromine,gepirone, moclobemide, physostigmine, nicotine, huperzine alpha, vitaminc, vitamin e, carotenoids, ginkgo biloba, statinsamphetamine, modafinil,desoxyn, methamphetamine, cocaine, arecoline, dexmethylphenidate,dextroamphetamine, methylphenidate, lisdexamfetamine dimesylate(vyvanse), mixed salts amphetamine, atomoxetine, clonidinehydrochloride, guanfacine hydrochloride, arecoline, pemoline, donepezil,tacrine, rivastigmine, memantine, lamotrigine, acamprosate,tetrabenazine, riluzole).

In certain embodiments any of the compositions described herein isformulated as a unit dosage formulation. In certain embodiments theactive agent(s) comprising the composition are independently formulatedas salts, esters, or prodrugs. In certain embodiments the composition isformulated for administration by a route selected from the groupconsisting of oral administration, transdermal administration,transnasal administration, intramuscular administration, rectaladministration, intravenous administration, intrathecal administration,intraperitoneal administration, administration in a subcutaneous depotformulation, and administration as an inhalant.

Also provided are methods of mitigating one or more symptoms of aneuropsychiatric disorder. The methods typically involve administeringto a subject in need thereof a benzoic acid, benzoic acid salt, orbenzoic acid derivative and/or a sorbic acid, sorbic acid salt, orsorbic acid derivative in conjunction with an NMDA enhancer and/or aglycine transporter inhibitor. In certain embodiments the compositioncomprises any of the drug combinations described herein. In certainembodiments the neuropsychiatric disorder is schizophrenia. In certainembodiments the neuropsychiatric disorder is bipolar disorder or mania,or hypomania. In certain embodiments the neuropsychiatric disorder ismild cognitive impairment, Alzheimer's disease and/or Parkinson'sdisease and/or dementia. In certain embodiments the neuropsychiatricdisorder is ataxia and/or spinocerebellar degeneration. In certainembodiments the neuropsychiatric disorder is autism or Asperger'sdisorder. In certain embodiments the neuropsychiatric disorder isdepression or dysthymia. In certain embodiments the neuropsychiatricdisorder is benign forgetfulness or mild cognitive impairment. Incertain embodiments the neuropsychiatric disorder is a childhoodlearning disorder (e.g., attention deficit disorder). In certainembodiments the neuropsychiatric disorder is close head injury. Incertain embodiments the neuropsychiatric disorder is anxiety disordersincluding obsessive compulsive disorder, generalized anxiety disorder,panic disorder, phobia, social phobia. In certain embodiments theneuropsychiatric disorder is close post-traumatic stress disorder. Incertain embodiments the neuropsychiatric disorder is substance abuseand/or substance dependence.

In certain embodiments any of the uses and/or methods described hereinexpressly exclude one or more neuropsychiatric disorders selected fromthe group consisting of schizophrenia, bipolar disorder, Alzheimer'sdisease, Parkinson's disease, dementia, ataxia, spinocerebellardegeneration, ADD, ADHD, depression, and mild cognitive impairment. Incertain embodiments the use benzoic acid, salt, ester, or other benzoicacid derivative and/or sorbic acid, salt, ester, or other sorbic acidderivative in the treatment of neurodegenerative conditions (e.g.,Alzheimer's disease, senile dementia of the Alzheimer type, etc.) isexcluded. In certain embodiments the use benzoic acid, salt, ester, orother benzoic acid derivative in the treatment of neurodegenerativeconditions (e.g., Alzheimer's disease, senile dementia of the Alzheimertype, etc.) is excluded.

Definitions

As used herein, the term “neuropsychiatric disorder” refers to a diseasehaving a pathophysiological component of attenuated NMDAreceptor-mediated neurotransmission. Examples of such disorders includeschizophrenia, bipolar disorder, Alzheimer's disease, dementia, autism,Asperger's disorder, depression, benign forgetfulness, mild cognitiveimpairment, childhood learning disorders, close head injury, ataxia,spinocerebellar degeneration, Parkinson's disease, general anxietydisorder, panic disorder, obsessive compulsive disorder, phobiaincluding social phobia, substance abuse, substance dependence, andattention deficit disorder.

As used herein, the term “schizophrenia” refers to a psychiatricdisorder that includes at least two of the following: delusions,hallucinations, disorganized speech, grossly disorganized or catatonicbehavior, or negative symptoms. Patients can be diagnosed asschizophrenic using the DSMIV criteria (APA, 1994, Diagnostic andStatistical Manual of 30 Mental Disorders (Fourth Edition), Washington,D.C.).

Bipolar disorder or manic-depressive disorder (also referred to abipolarism or manic depression) is a psychiatric diagnosis thatdescribes a category of mood disorders defined by the presence of one ormore episodes of abnormally elevated mood clinically referred to asmania or, if milder, hypomania. Individuals who experience manicepisodes also commonly experience depressive episodes or symptoms, ormixed episodes in which features of both mania and depression arepresent at the same time. These episodes are usually separated byperiods of “normal” mood, but in some individuals, depression and maniamay rapidly alternate, known as rapid cycling. Extreme manic episodescan sometimes lead to psychotic symptoms such as delusions andhallucinations. The disorder has been subdivided into bipolar I, bipolarII, cyclothymia, and other types, based on the nature and severity ofmood episodes experienced; the range is often described as the bipolarspectrum. Patients can be diagnosed as having bipolar disorder using theDSMIV criteria.

The term “Alzheimer's Disease” refers to a progressive mentaldeterioration manifested by memory loss, confusion and disorientationbeginning in late middle life and typically resulting in death in fiveto ten years. Pathologically, Alzheimer's Disease can be characterizedby thickening, conglutination, and distortion of the intracellularneurofibrils, neurofibrillary tangles and senile plaques composed ofgranular or filamentous argentophilic masses with an amyloid core.Methods for diagnosing Alzheimer's Disease are known in the art. Forexample, the National Institute of Neurological and CommunicativeDisorders and Stroke-Alzheimer's Disease—and the Alzheimer's Disease andRelated Disorders Association (NINCDS-ADRDA) criteria can be used todiagnose Alzheimer's Disease (McKhann et al. (1984) Neurology 34:939-944). The patient's cognitive function can be assessed by theAlzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog; Rosenet al. (1984) Am. J. Psychiatry 141: 1356-1364).

Dementia is the progressive decline in cognitive function due to damageor disease in the brain beyond what might be expected from normal aging.Patients can be diagnosed as suffering from dementia by using the DSM-IVcriteria. Dementia also includes mild cognitive impairment (MCI, alsoknown as incipient dementia, or isolated memory impairment) which is adiagnosis given to individuals who have cognitive impairments beyondthat expected for their age and education, but that do not interferesignificantly with their daily activities. It is considered to be theboundary or transitional stage between normal aging and dementia. Theseindividuals tend to progress to probable Alzheimer's disease at a rateof approximately 10% to 15% per year. Additionally, when individualshave impairments in domains other than memory it is classified asnon-amnestic single- or multiple-domain MCI and these individuals arebelieved to be more likely to convert to other dementias (i.e. dementiawith Lewy bodies).

As used herein, the term “autism” refers to a state of mentalintroversion characterized by morbid self-absorption, social failure,language delay, and stereotyped behavior. Patients can be diagnosed assuffering from autism by using the DSM-IV criteria.

Asperger's disorder (syndrome) is an autism spectrum disorder, andpeople with it therefore show significant difficulties in socialinteraction, along with restricted and repetitive patterns of behaviorand interests. It differs from other autism spectrum disorders by itsrelative preservation of linguistic and cognitive development. Althoughnot required for diagnosis, physical clumsiness and atypical use oflanguage are frequently reported. Patients can be diagnosed as sufferingfrom Asperger's disorder by using the DSM-IV criteria.

As used herein, the term “depression” refers to a clinical syndrome thatincludes a persistent sad mood or loss of interest in activities, whichlasts for at least two weeks in the absence of treatment. The DSM-IVcriteria can be used to diagnose patients as suffering from depression.

The term “benign forgetfulness,” as used herein, refers to a mildtendency to be unable to retrieve or recall information that was onceregistered, learned, and stored in memory (e.g., an inability toremember where one placed one's keys or parked one's car). Benignforgetfulness typically affects individuals after 40 years of age andcan be recognized by standard assessment instruments such as theWechsler Memory Scale (Russell (1975) J. Consult Clin. Psychol. 43:800-809).

As used herein, the term “childhood learning disorders” refers to animpaired ability to learn, as experienced by certain children. Suchlearning disorders can be diagnosed by using the DSM-IV criteria.

The term “close head injury,” as used herein, refers to a clinicalcondition after head injury or trauma which condition can becharacterized by cognitive and memory impairment. Such a condition canbe diagnosed as “amnestic disorder due to a general medical condition”according to DSM-IV.

The term “attention deficit disorder,” as used herein, refers to atdisorder that is most commonly exhibited by children and which can becharacterized by increased motor activity and a decreased attentionspan. The DSM-IV criteria can be used to diagnose attention deficitdisorder.

The terms “D-serine” and “D-alanine” refer to the D isomers of the aminoacids serine and alanine, respectively. As D isomers, rather than Lisomers, these amino acids are not naturally found in proteins.

“Negative” symptoms of schizophrenia include affect blunting, anergia,alogia and social withdrawal, which can be measured using SANS (theScales for the Assessment of Negative Symptoms; see Andreasen (1983)Scales for the Assessment of Negative Symptoms (SANS), Iowa City, Iowa).

“Positive” symptoms of schizophrenia include delusion and hallucination,which can be measured using PANSS (Positive and Negative Syndrome Scale;see Kay et al. (1987) Schizophrenia Bulletin 13: 261-276).

“Cognitive” symptoms of schizophrenia include impairment in obtaining,organizing, and using intellectual knowledge which can be measured bythe Positive and Negative Syndrome Scale-cognitive subscale(PANSS-cognitive subscale) (Lindenmayer et al. (1994) J. Nerv. Ment.Dis. 182: 631-638) or with cognitive tasks such as the Wisconsin CardSorting Test and battery of Measurement and Treatment Research toImprove Cognition in Schizophrenia (MATRICS,“www.matrics.ucla.edu/matrics-psychometrics-frame.htm”).

A “full” agonist of the NMDA receptor is a compound that produces amaximal response at full receptor occupancy.

A “partial” agonist of the NMDA receptor is a compound that produces alower maximal response at full receptor occupancy than do full agonists.

A “glycine uptake inhibitor of the NMDA receptor” is a compound thatinhibits the re-uptake of glycine and increases the availability ofglycine for the NMDA receptor (e.g., N-methylglycine).

The phrase “in conjunction with” when used in reference to the use ofone or more drugs (active agents) described herein indicates that thedrug(s) and the active agent(s) are administered so that there is atleast some chronological overlap in their physiological activity on theorganism. Thus the active agent(s) can be administered simultaneouslyand/or sequentially. In sequential administration there may even be somesubstantial delay (e.g., minutes or even hours or days) beforeadministration of the second moiety as long as the first administereddrug/agent has exerted some physiological alteration on the organismwhen the second administered agent is administered or becomes active inthe organism.

The phrase “enhancing the in vivo activity” or “enhancing the apparentactivity” when referring to the agents described herein indicates thatthe agents, when administered in conjunction with a pharmaceuticalproduce a greater biological response in the organism than the samedosage administered without the agent.

The term mammal includes essentially any mammal including, but notlimited to dogs, cats, sheep, cattle, horses, goats, mice, rats,rabbits, hamsters, pigs, monkeys and other non-human primates, andhumans. Thus, veterinary as well as medical applications of thisinvention are contemplated.

“Ataxia” is a neurological sign and symptom consisting of gross lack ofcoordination of muscle movements.

“Spinocerebellar degeneration” refers to a group of genetic disorderscharacterized by slowly progressive incoordination of gait and oftenassociated with poor coordination of hands, speech, and eye movements.Frequently, atrophy of the cerebellum occurs. As with other forms ofataxia, results in unsteady and clumsy motion of the body due to afailure of the fine coordination of muscle movements, along with othersymptoms.

“Parkinson's disease” belongs to a group of chronic and progressiveconditions called movement disorders. It is characterized by musclerigidity, tremor, a slowing of physical movement (bradykinesia) and, inextreme cases, a loss of physical movement (akinesia). The primarysymptoms are the results of decreased stimulation of the motor cortex bythe basal ganglia, normally caused by the insufficient formation andaction of dopamine, which is produced in the dopaminergic neurons of thebrain. Secondary symptoms may include high level cognitive dysfunctionand subtle language problems.

“Obsessive compulsive disorder” is a mental disorder most commonlycharacterized by a intrusive, repetitive thoughts resulting incompulsive behaviors and mental acts that the person feels driven toperform, according to rules that must be applied rigidly, aimed atpreventing some imagined dreaded event; however, these behaviors ormental acts are not connected to the imagined dreaded event. Patientscan be diagnosed as having obsessive compulsive disorder using the DSMIVcriteria.

Generalized anxiety disorder (GAD) is an anxiety disorder that ischaracterized by excessive, uncontrollable and often irrational worryabout everyday things that is disproportionate to the actual source ofworry. This excessive worry often interferes with daily functioning, asindividuals suffering GAD typically anticipate disaster, and are overlyconcerned about everyday matters such as health issues, money, death,family problems, friend problems or work difficulties. They oftenexhibit a variety of physical symptoms, including fatigue, fidgeting,headaches, nausea, numbness in hands and feet, muscle tension, muscleaches, difficulty swallowing, bouts of difficulty breathing, trembling,twitching, irritability, sweating, insomnia, hot flashes, and rashes.Patients can be diagnosed as suffering from GAD by using the DSM-IVcriteria.

Panic disorder is an anxiety disorder characterized by recurring severepanic attacks. It may also include significant behavioral change lastingat least a month and of ongoing worry about the implications or concernabout having other attacks. The latter are called anticipatory attacks.Patients can be diagnosed as suffering from panic disorder by using theDSM-IV criteria.

Phobia is an intense and persistent fear of certain situations,activities, things, animals, or people. The main symptom of thisdisorder is the excessive and unreasonable desire to avoid the fearedsubject. When the fear is beyond one's control, and if the fear isinterfering with daily life, then a diagnosis under one of the anxietydisorders can be made. Patients can be diagnosed as suffering fromphobia by using the DSM-IV criteria.

Social Phobia is anxiety (emotional discomfort, fear, apprehension, orworry) about social situations, interactions with others, and beingevaluated or scrutinized by other people. It occurs early in childhoodas a normal part of the development of social functioning, but may gounnoticed until adolescence or may surface in adulthood. People vary inhow often they experience social anxiety and in which kinds ofsituations. Patients can be diagnosed as suffering from social phobia byusing the DSM-IV criteria.

“Substance abuse”, the disorder is characterized by a pattern ofcontinued pathological use of a medication, non-medically indicated drugor toxin, that results in repeated adverse social consequences relatedto drug use, such as failure to meet work, family, or schoolobligations, interpersonal conflicts, or legal problems. The substancecan be, but not limited to: Alcohol, Amphetamine (or amphetamine-like),Cannabis, Cocaine, Hallucinogen, Inhalant, Nicotine, Opioid,Phencyclidine (or phencyclidine-like), Sedative, hypnotic, or anxiolyticor Polysubstance dependence. Patients can be diagnosed as substanceabuse using the DSMIV criteria (APA, 1994, Diagnostic and StatisticalManual of Mental Disorders (Fourth Edition), Washington, D.C.). When anindividual persists in use of alcohol or other drugs despite problemsrelated to use of the substance. Compulsive and repetitive use mayresult in tolerance to the effect of the drug and withdrawal symptomswhen use is reduced or stopped. This, along with Substance Abuse areconsidered Substance Use Disorders The substance can be, but not limitedto: Alcohol, Amphetamine (or amphetamine-like), Cannabis, Cocaine,Hallucinogen, Inhalant, Nicotine, Opioid, Phencyclidine (orphencyclidine-like), Sedative, hypnotic, or anxiolytic or Polysubstancedependence. Substance dependence can be diagnosed with physiologicaldependence, evidence of tolerance or withdrawal. Patients can bediagnosed as substance dependence using the DSMIV criteria (APA, 1994,Diagnostic and Statistical Manual of 30 Mental Disorders (FourthEdition), Washington, D.C.).

A “neurophanmaceutical” refers to a drug used to treat neuropsychiatric,neuropsychological, or nervous-system disorders including, but notlimited to depression, schizophrenial, bipolar disorder, attentiondeficit hyperactivity disorder (ADHD), schizophrenia, Alzheimer'sdisease, and the like.

Where Markush groups are indicated herein (e.g., “where x is selectedfrom the group consisting of A, B, and C”) subgroups are contemplatedcomprising any one or more of the elements making up the Markush group(e.g., A and B, A and C, B and C, A alone, B alone, C alone, for MarkushGroup A, B, and C).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. The difference of startle responses between the initial and thelast group of trials of single acoustic stimulus were considered theamount of habituation. Three groups of mice each were treated withsarcosine (200 mg/kg), benzoate (100 mg/kg), a combination of bothsarcosine and benzoate. Amphetamatine (10 mg/kg) was administered 30minutes before the experiments. There was no difference in thehabituation at baseline across the groups (left group). Combinationtreatments (right) induce a stronger habituation effect than benzoate(left) or sarcosine treatment alone (middle). However, the effect ofbenzoate is close to the effect seen in the combination treatment. Thesame trend of habituation (combination treatment>benzoate>sarcosine) wasevident when amphetamine was administered and disrupted the habituation(right group). The combination treatment corrected theamphetamine-induced disruption of habituation back to a normal statewhile single treatment of NMG or benzoate only partially corrected thedeficit (right group). The effect of benzoate, however, was better thansarcosine and close to that seen in the combination treatment.

FIG. 2. Four groups of 10 mice each were treated with sarcosine (200mg/kg), benzoate (100 mg/kg), a combination of both sarcosine andbenzoate (same doses as the individual treatment), or with vehicle forone week before the test. The mice continued to receive the drug untilone week later when amphetamatine (10 mg/kg) was administered 30 minutesbefore the experiments. For PPI, stronger prepulse inhibited pulseresponse more (inhibition of 525 Hz>487 Hz>468 Hz). Amphetaminedisrupted the inhibition in all treatments. For example, in 487 Hzparadigm, the disruption by amphetamine is most pronounced invehicle-treated mice (left column), partially corrected by eithersarcosine (NMG) or benzoate (middle 2 columns) and was best corrected bythe combination treatment (right column).

FIG. 3. Six weeks of adjunctive benzoate vs. placebo treatment inpatients receiving risperidone treatment, at weeks 0, 2, 4, and 6,respectively. BE, benzoate, PANSS total, Positive and Negative SyndromeScale total score; PANSS-positive, Positive and Negative SyndromeScale-positive subscale score; SANS, Scales for the Assessment ofNegative symptoms.

DETAILED DESCRIPTION

In various embodiments methods are provided for treating a patientdiagnosed as suffering from a neuropsychiatric disorder or at high riskfor a neuropsychiatric disorder, particularly a disorder characterizedby a deficit in neurotransmission via the NMDA receptor (e.g.,schizophrenia, bipolar disorder, Alzheimer's Disease, dementia, mildcognitive impairment, autism, Asperger's disorder, depression, benignforgetfulness, childhood learning disorders, close head injury, andattention deficit disorder, ataxia, spinocerebellar degeneration,Parkinson's disease, obsessive compulsive disorder (OCD), phobia, socialphobia, substance abuse, and substance dependence). As described above,a variety of methods for diagnosing these disorders are known to thoseof skill in the art of clinical psychiatry, and any conventionaldiagnostic method can be used in conjunction with the invention.

In various embodiments this the compositions and methods describedherein pertain to the use of “combination” therapies, where the subjectsare administered a combination of one or more neuropharmaceuticals(e.g., an antipsychotic, an antidepressant, a phsychostimulant, a moodstablizer, an anxiolytic, an Alzheimer's disease therapeutic, otherpsychotropics), and/or an NMDA (N-methyl-D-aspartate)-Enhancer, and/or aglycine transporter inhibitor, and/or a D-amino Acid Oxidase Inhibitor(DAAOI). In certain embodiments the combination therapy comprises acombination of an NMDA (N-methyl-D-aspartate)-Enhancer, and/or a GlycineTransporter Inhibitor, and/or a DAAOI inhibitor. In certain embodimentsthe administration of at least two of these agents in conjunction witheach other is contemplated, and in certain embodiments, theadministration of all three agents in conjunction with each other iscontemplated. In various embodiments the agents can be utilizedindividually as well.

It was also a surprising discovery that DAAOI inhibitors (especiallysorbic acid and/or benzoic acid and derivatives thereof) when usedindividually or in combination with each other are capable of mitigatingone or more symptoms of a neuropsychiatric disorder. In addition, theyare capable of enhancing the activity of neuropharmaceuticals (e.g.,antipsychotics, antidepressants, ADHD medications, etc.). Accordingly,in certain embodiments, compositions that provide a prophylactically ortherapeutically active amount of benzoic acid, a benzoic acid salt, abenzoic acid ester, or other benzoic acid derivative, and/or sorbicacid, a sorbic acid salt, a sorbic acid ester, or other sorbic acidderivative are provided. In various methods such compositions can beused for the treatment of a neuropsychiatric disorder and/or for themanufacture for a medicament for the treatment of a neuropsychiatricdisorder.

In certain other embodiments, methods are contemplated that provided forthe use of one or more D-amino Acid Oxidase Inhibitors in conjunctionwith one or more neuropharmaceuticals. In this regard, in certainpreferred embodiments, the DAAOI comprises benzoic acid, a benzoic acidsalt, a benzoic acid ester, or other benzoic acid derivative, and/orsorbic acid, a sorbic acid salt, a sorbic acid ester, or other sorbicacid derivative. Similarly, compositions comprising a combination ofbenzoic acid, a benzoic acid salt, a benzoic acid ester, or otherbenzoic acid derivative, and/or sorbic acid, a sorbic acid salt, asorbic acid ester, or other sorbic acid derivative, and aneuropharmaceutical (e.g., an antipsychotic, an antidepressant, an ADHDmedication, etc.) are contemplated. In addition kits comprising ofbenzoic acid, a benzoic acid salt, a benzoic acid ester, or otherbenzoic acid derivative, and/or sorbic acid, a sorbic acid salt, asorbic acid ester, or other sorbic acid derivative are contemplated. Invarious embodiments the DAAOI and the neuropharmaceutical can beprovided in separate containers. In certain embodiments the DAAOI andthe neuropharmaceutical can be provided in the same container (e.g., asa combined/compound formulation).

Previous treatments using an NMDA enhancer or a glycine transporterinhibitor alone have had limited efficacy. It was discovered that theuse of a DAAOI alone, especially a benzoic acid, benzoic acid salt,benzoic acid ester or other benzoic acid derivative and/or sorbic acid,a sorbic acid salt, a sorbic acid ester or other sorbic acid derivativecan result in unexpected and surprising improvement in subjectsdiagnosed with a neuropsychiatric disorders. Accordingly in certainembodiments, the use of a benzoic acid salt, or other derivative and/ora sorbic acid, salt, or other derivative in the treatment of aneuropsychiatric disorder (e.g., schizophrenia, bipolar disorder,Alzheimer's disease, dementia, autism, Asperger's disorder, depression,benign forgetfulness, mild cognitive impairment, childhood learningdisorders, close head injury, ataxia, spinocerebellar degeneration,Parkinson's disease, general anxiety disorder, panic disorder, obsessivecompulsive disorder, phobia including social phobia, substance abuse,substance dependence, attention deficit disorder, etc.) arecontemplated. Similarly medicaments comprising a benzoic acid, benzoicacid salt, benzoic acid ester or other benzoic acid derivative and/orsorbic acid, a sorbic acid salt, a sorbic acid ester or other sorbicacid derivative in an amount sufficient to mitigate one or more symptomsof a neuropsychiatric disorder are contemplated.

In addition, it was discovered that combination treatment(s), e.g., abenzoic acid, benzoic acid salt, benzoic acid ester or other benzoicacid derivative and/or sorbic acid, a sorbic acid salt, a sorbic acidester or other sorbic acid derivative in combination with one or moreneuropharmaceuticals, results in unexpected and surprising improvementin subjects diagnosed with a neuropsychiatric disorders. Thus methodscomprising the administration of benzoic acid, a benzoic acid salt, abenzoic acid ester, or other benzoic acid derivative, and/or sorbicacid, a sorbic acid salt, a sorbic acid ester, or other sorbic acidderivative, in conjunction with one or more neuropharmaceuticals arecontemplated. Similarly medicaments comprising a benzoic acid, benzoicacid salt, benzoic acid ester or other benzoic acid derivative and/orsorbic acid, a sorbic acid salt, a sorbic acid ester or other sorbicacid derivative and one or more neuropharmaceuticals (e.g., agents forthe treatment of a condition such as schizophrenia, bipolar disorder,Alzheimer's disease, dementia, autism, Asperger's disorder, depression,benign forgetfulness, mild cognitive impairment, childhood learningdisorders, close head injury, ataxia, spinocerebellar degeneration,Parkinson's disease, general anxiety disorder, panic disorder, obsessivecompulsive disorder, phobia including social phobia, substance abuse,substance dependence, attention deficit disorder, etc.) arecontemplated. Typically, the benzoic acid, benzoic acid salt, benzoicacid ester, or other benzoic acid derivative, and/or sorbic acid, sorbicacid salt, sorbic acid ester, or other sorbic acid derivative, isprovided in the method or medicament in an amount sufficient to enhancethe efficacy of the neuropharmaceutical.

Without being bound to a particular theory, it is believed that theDAAOI enhances the levels of both D-serine and D-alanine which areagonists of NMDA receptor and have been shown by the inventor to bebeneficial for patients with schizophrenia and other disorders. It canhelp a wide variety of patients with cognitive impairment and othermental or behavioral symptoms. The combination therapies boost the NMDAand/or neuropharmaceutical activity and benefit subjects more thansingle agent treatments (e.g., antipsychotic drug, antidepressant,anxiolytic, mood stabilizer, psychotropic medication for attentiondeficit and hyperactivity disorder, drug for dementia, and the like).

Accordingly, in certain preferred embodiments, “combination” therapiesare contemplated, where the subjects are administered a benzoic acid, abenzoic acid salt, a benzoic acid ester, or another benzoic acidderivative, and/or a sorbic acid, a sorbic acid salt, sorbic acid ester,or another sorbic acid derivative, in conjunction with aneuropharmaceutical (e.g., a therapeutic agent selected from the groupconsisting of an antipsychotic, an antidepressant, a phsychostimulant, amood stabilizer, an anxiolytic, an Alzheimer's disease therapeutic,and/or other psychotropic for the treatment of a neuropsychiatricdisorder).

In certain embodiments (e.g., for the treatment of schizophrenia,bipolar disorder, and the like) the neuropharmaceutical used in the“combination” treatment is an antipsychotic drug. In certain embodimentsthe antipsychotic drug is a drug selected from the group consisting ofbutyrophenone (e.g., Haloperidol (HALDOL®), phenothiazine (e.g.,chlorpromazine (THORAZINE®), fluphenazine (PROLIXIN®), perphenazine(TRILAFON®), prochlorperazine (COMPAZINE®), thioridazine (MELLARIL®),trifluoperazine (STELAZINE®), mesoridazine, promazine, triflupromazine(VESPRIN®), levomepromazine (NOZINAN®), promethazine (PHENERGAN®),thioxanthene (e.g., chlorprothixene, flupenthixol (DEPIXOL®, FLUANXOL®),thiothixene (NAVANE®), zuclopenthixol (CLOPIXOL®, ACUPHASE®), clozapine(CLOZARIL®), olanzapine (ZYPREXA®), risperidone (RISPERDAL®, RISPERDALCONSTA®), quetiapine (SEROQUEL®), ziprasidone (GEODON®), amisulpride(SOLIAN®), asenapine, paliperidone, Aripiprazole (ABILIFY®), dopaminepartial agonists (BIFEPRUNOX®, NORCLOZAPINE® (ACP-104)), lamotrigine(LAMICTAL®), memantine (AXURA®, AKATINOL®, NAMENDA®, EBIXA®, ABIXA®),tetrabenazine (NITOMAN®, XENAZINE®), cannabidiol, LY2140023, and thelike).

In certain embodiments (e.g., for the treatment of depression, panicdisorder, social phobial, GAD, etc.) the neuropharmaceutical used in the“combination treatment” comprises an antidepressant and/or moodstabilizer. In certain embodiments the antidepressant comprises amonoamine oxidase inhibitor (MAOI), a tricyclic antidepressant (TCA), atetracyclic antidepressant (TeCA), a selective serotonin reuptakeinhibitor (SSRI), a noradrenergic and specific serotonergicantidepressant (NASSA), a norepinephrine (noradrenaline) reuptakeinhibitor, a norepinephrine-dopamine reuptake inhibitor, and/or aserotonin-norepinephrine reuptake inhibitor (SNRI).

In certain embodiments the antidepressant is a drug selected from thegroup consisting of a tricyclic antidepressant (e.g., IMIPRAMINE® andvariants), a selective serotonin reuptake inhibitor (SSRI) (e.g.,fluoxetine (PROZAC®), paroxetine (PAXIL®, SEROXAT®), escitalopram(LEXAPRO®, ESIPRAM®), citalopram (CELEXA®), sertraline (ZOLOFT®),fluvoxamine (LUVOX®)), a serotonin-norepinephrine reuptake inhibitor(SNRI) (e.g., venlafaxine (EFFEXOR®)), milnacipram and duloxetine(CYMBALTA®), a noradrenergic and specific serotonergic antidepressant(NASSA) (e.g., mirtazapine (AVANZA®, ZISPIN®, REMERON®), mianserin), anorepinephrine (noradrenaline) reuptake inhibitor (NRI) (e.g.,reboxetine (EDRONAX®)), a norepinephrine-dopamine reuptake inhibitors(e.g., bupropion (WELLBUTRIN®, ZYBAN®)), Amitriptyline, Nortriptiline,Protriptyline, Desipramine, Trimipramine, Amoxapine, Bupropion,Bupropion SR, S-Citalopram, Clomipramine, Desipramine, Doxepin,Isocarboxazid, Velafaxine XR, Tranylcypromine, Trazodone, Nefazodone,Phenelzine, Lamatrogine, Lithium, Topiramate, Gabapentin, Carbamazepine,Oxacarbazepine, Valporate, Maprotiline, Mirtazapine, Brofaromine,Gepirone, Moclobemide, isoniazid, iproniazid, and the like.

In certain embodiments (e.g., for the treatment of ADD or ADHD), theneuropharmaceutical used in the “combination treatment” comprises anagent for the treatment of ADD and/or ADHD. In certain suitable ADHDmedications include, but are not limited to an ADHD medication selectedfrom the group consisting of Statins Amphetamine, Modafinil, Desoxyn,Methamphetamine, cocaine, arecoline, Dexmethylphenidate (Focalin,Focalin XR), dextroamphetamine (Dexedrine, Dexedrine Spansules,Dextroamphetamine ER, Dextrostat), methylphenidate (Concerta, Daytrana,Metadate CD, Metadate ER, Methylin, Methylin ER, Ritalin, Ritalin-LA,Ritalin-SR), lisdexamfetamine dimesylate (Vyvanse), mixed saltsamphetamine (Adderall, Adderall XR), Atomoxetine (Strattera), clonidinehydrochloride (Catapres), guanfacine hydrochloride (Tenex), arecoline,and Pemoline.

In certain embodiments (e.g., for the treatment of a cognitive disorder,and/or a condition characterized by neurodegeneration (e.g. Alzheimer'sdisease, Parkinson's disease, etc.)) the neuropharmaceutical used in the“combination treatment” can include, but is not limited to an agentselected from the group consisting of Donepezil, Tacrine, Rivastigmine,memantine (AXURA®, AKATINOL®, NAMENDA®, EBIXA®, ABIXA®), aricept,physostigmine, nicotine, arecoline, huperzine alpha, selegiline,Rilutek® (riluzole), vitamin c, vitamin e, carotenoids, ginkgo biloba,and the like.

In various embodiments the benzoic acid, benzoic acid salt, orderivative thereof, and/or sorbic acid, a sorbic acid salt, or aderivative thereof, can be administered separately before, after, orsimultaneously with one or more the neuropharmaceuticals. For example,the benzoic acid, benzoic acid salt, or derivative thereof, and/orsorbic acid, a sorbic acid salt, or a derivative thereof can be providedin one formulation and the neuropharmaceutical(s) in anotherformulation.

In certain embodiments where the benzoic acid, benzoic acid salt, orderivative thereof, and/or sorbic acid, a sorbic acid salt, or aderivative thereof is administered simultaneously with theneuropharmaceuticals they can be provided as a combined formulation.Accordingly, in certain embodiments, corresponding combinationtherapeutics are also provided. Thus, in certain embodiments, apharmaceutical composition is provided comprising a benzoic acid,benzoic acid salt, benzoic acid ester, or other benzoic acid derivativeand/or sorbic acid, a sorbic acid salt, a sorbic acid ester, or othersorbic acid derivative and a neuropharmaceutical (e.g, anantidepressant, an anxiolytic, an antipsychotic drug, etc.), where thebenzoic acid, benzoic acid salt, benzoic acid ester, or other benzoicacid derivative and/or sorbic acid, a sorbic acid salt, a sorbic acidester, or other sorbic acid is present in an amount sufficient toincrease the efficacy of neuropharmaceutical (e.g., risperidone,olanzapine, etc.). Also provided are formulations comprising a benzoicacid, benzoic acid salt, or derivative thereof (e.g., a benzoate, and/orsorbic acid, sorbic acid salt, or a derivative thereof (e.g., asorbate); and an antidepressant drug, where the benzoic acid, benzoicacid salt, or derivative thereof, and/or thereof, and/or sorbic acid,sorbic acid salt, or a derivative thereof, is present in a concentrationsufficient to increase the efficacy of the antidepressant drug (e.g.,sertraline hydrochloride, fluoxetine hydrochloride, etc.).

Also provided are formulations comprising the benzoic acid, benzoic acidsalt, benzoic acid ester, or other benzoic acid derivative, and/orsorbic acid, sorbic acid salt, sorbic acid ester, or other sorbic acidderivative, and a neuropharmaceutical e.g., as described above.Typically, the benzoic acid, benzoic acid salt, benzoic acid ester, orother benzoic acid derivative, and/or sorbic acid, sorbic acid salt,sorbic acid ester, or other sorbic acid derivative, is present in anamount sufficient to increase the efficacy of the neuropharmaceutical(e.g., Aricept, memantine, etc.).

In certain embodiments the combination formulation for the treatment ofschizophrenia, bipolar disorder, and the like comprises a combination ofbenzoic acid, benzoic acid salt, benzoic acid ester, or other benzoicacid derivative, and/or sorbic acid, sorbic acid salt, sorbic acidester, or other sorbic acid derivative and an antipsychotic drug.Suitable antipsychotic drugs include, but are not limited to theantipsychotic drugs described above.

In certain embodiments the combination formulation for the treatment ofschizophrenia, bipolar disorder, and the like comprises a combination ofdepression, panic disorder, social phobial, GAD, and the like comprisesa combination of benzoic acid, benzoic acid salt, benzoic acid ester, orother benzoic acid derivative, and/or sorbic acid, sorbic acid salt,sorbic acid ester, or other sorbic acid derivative and an antidepressantand/or mood stabilizer. Suitable antidepressants and mood stabilizersinclude, but are not limited to the antidepressants and mood stabilizersdescribed above.

In certain embodiments the combination formulation for the treatment ofADD and/or ADHD, and the like comprises a combination of benzoic acid,benzoic acid salt, benzoic acid ester, or other benzoic acid derivative,and/or sorbic acid, sorbic acid salt, sorbic acid ester, or other sorbicacid derivative and an agent for the treatment of ADD and/or ADHD.Suitable agents for the treatment of ADD and/or ADHD include, but arenot limited to the agents for the treatment of ADD and/or ADHD describedabove.

In certain embodiments the combination formulation for the treatment ofa cognitive disorder, and/or a condition characterized byneurodegeneration (e.g. Alzheimer's disease, Parkinson's disease, etc.)comprises a combination of benzoic acid, benzoic acid salt, benzoic acidester, or other benzoic acid derivative, and/or sorbic acid, sorbic acidsalt, sorbic acid ester, or other sorbic acid derivative and an agentfor the treatment of a cognitive disorder, and/or a conditioncharacterized by neurodegeneration. Suitable agents for the treatment ofa cognitive disorder, and/or a condition characterized byneurodegeneration include, but are not limited to the agents for thetreatment of a cognitive disorder, and/or a condition characterized byneurodegeneration described above.

Typically, in various embodiments, the benzoic acid, benzoic acid salt,or derivative thereof (e.g., a benzoate), and/or sorbic acid, a sorbicacid salt, or a derivative thereof, is present in an amount sufficientto enhance therapeutic efficacy of the neuropharmaceutical rather thanas a preservative, and/or melting point lowering agent, and/orstabilizer, and/or a lubricant, and/or a stabilizer, etc. In effect, thebenzoic acid, benzoic acid salt, or derivative thereof, and/or sorbicacid, sorbic acid salt, or a derivative thereof, is an active agent.Thus, in various embodiments the benzoic acid, benzoic acid salt,benzoic acid ester, or other benzoic acid derivative, and/or sorbicacid, sorbic acid salt, sorbic acid ester, or other sorbic acidderivative, is not substantially present as an acid addition salt of theneuropharmaceutical (or at least the majority of the benzoic or sorbicacid or derivative thereof) is not present as an acid salt addition saltof the neuropharmaceutical. Similarly, in certain embodiments thebenzoic acid, benzoic acid salt, benzoic acid ester, or other benzoicacid derivative, and/or sorbic acid, sorbic acid salt, sorbic acidester, or other sorbic acid derivative, (or at least the majority of thebenzoic or sorbic acid or derivative thereof) is not present as aco-crystal of the neuropharmaceutical.

In certain compositions, and treatments, the ratio of benzoic acid,benzoic acid salt, benzoic acid ester, or other benzoic acid derivative,and/or sorbic acid, sorbic acid salt, sorbic acid ester, or other sorbicacid derivative, to neuropharmaceutical (e.g., antidepressant,antipsychotic drug, therapeutic for attention deficit and hyperactivitydisorder, therapeutic for dementia, and/or mood stabilizer, or otherpharmaceutical) is stoichiometrically greater than 2:1, preferablygreater than about 3:1, 4:1, 5:1, 6;1, 7:1, 8:1, 9;1, 10:1, 15:1, or20:1. In certain embodiments the benzoic acid, benzoic acid salt,benzoic acid ester, or other benzoic acid derivative, and/or sorbicacid, sorbic acid salt, sorbic acid ester, or other sorbic acidderivative, combinations expressly exclude a psychoactive pharmaceuticalother than an antipsychotic and/or antidepressant and/or therapeutic forattention deficit and hyperactivity disorder and/or therapeutic fordementia.

In various embodiments the benzoic acid, benzoic acid salt, benzoic acidester, or other benzoic acid derivative, and/or sorbic acid, sorbic acidsalt, sorbic acid ester, or other sorbic acid derivative, is typicallyprovided in an amount sufficient to improve the therapeutic efficacy ofthe neuropharmaceutical (e.g, antipsychotic and/or antidepressant and/ortherapeutic for attention deficit and hyperactivity disorder and/ortherapeutic for dementia). Thus, typical dosages of the benzoic acid,benzoic acid salt, benzoic acid ester, or other benzoic acid derivative,and/or sorbic acid, sorbic acid salt, sorbic acid ester, or other sorbicacid derivative, range from range is from about 5 mg, to about 500grams, more preferably about 25 mg to about 400, 300 grams, 200 grams,or 100 grams, still more preferably about 50 mg to 50 or to 100 or 150grams.

Most of the neuropsychiatric disorders present with cognitive deficits,behavioral and mental symptoms. The various treatment strategiesdescribed herein can be applied to most if not all of them including,for example, learning disorder, attention deficit and hyperactivitydisorder, schizophrenia, bipolar disorder, depression, Alzheimer'sDisease, autism, benign forgetfulness, close head injury, dementia, mildcognitive impairment, ataxia, spinocerebellar degeneration, Parkinson'sdisease, obsessive compulsive disorder (OCD), phobia, social phobia,generalized anxiety disorder (GAD), panic disorder, substance abuse, andsubstance dependence. In addition to their benefits for human subjects,the treatments described herein can be used in veterinary applications(e.g., to canines, felines, equines, bovines, porcines, etc.) withtreatment of household pets (e.g., canine, feline) being of considerableinterest. In addition, the combination treatments described herein canimprove cognition in animal models of learning and model ofschizophrenia, depression, anxiety, and the like.

In certain embodiments the treatment methods of the invention entailadministering to a subject in need thereof (e.g., a patient diagnosed ashaving or at risk for a neuropsychiatric disorder) one or more apharmaceutical compositions containing a therapeutically effectiveamount(s) of (i) an NMDA (N-methyl-D-aspartate)-Enhancer, and/or (ii) aglycine transporter inhibitor, and/or (iii) a D-amino Acid OxidaseInhibitor (DAAOI). Where combinations of two or all three of theseagents are utilized they can be administered separately (simultaneouslyor sequentially), in a single “combination” formulation, or insimultaneously or sequentially a combination formulation comprising twoagents and a second formulation comprising a single agent.

The effective doses of the active agent(s) (of an NMDA(N-methyl-D-aspartate)-Enhancer, and/or Glycine Transporter Inhibitor,and/or D-amino Acid Oxidase Inhibitor (DAAOI)) can vary, depending uponfactors such as the condition of the patient, the severity of thesymptoms of the disorder, and the manner in which the pharmaceuticalcomposition is administered. In various embodiments, for human patients,the effective unit dose of typical compounds include: DAAOI (e.g.,benzoate, range of 50 mg-150 grams), NMDA enhancers (D-serine, range of50 mg-50 grams; D-alanine, range 1-150 grams), glycine transporterinhibitor (for example: sarcone, range 50 mg-50 grams); includingDAAOI+NMDA enhancer, DAAOI+glycine transporter inhibitor, NMDAenhancers+glycine transporter inhibitor or three classes of compoundtogether.

In various embodiments, then, effective doses of each of the activeagent(s) ranges from 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, or 500 mg, 300g, 200 g, 150 g, 100 g, 50 g, 25 g, 10 g, 5 g, or 1 g depending offactors including, but not limited to 150 g. In certain embodiments thecompounds and compositions of the present invention can be administeredto a patient at dosage levels in the range of about 0.1 to about 1,000mg per day. For a normal human adult having a body weight of about 70kilograms, it is estimated that a dosage in the range of about 0.01 toabout 100 mg per kilogram of body weight per day is sufficient. Thespecific dosage used, however, can vary. For example, the dosage candepend on a numbers of factors including the requirements of thepatient, the severity of the condition being treated, and thepharmacological activity of the compound being used. The determinationof optimum dosages for a particular patient is well-known to thoseskilled in the art. The amount of active ingredient(s) that may becombined with the carrier materials to produce a single dosage form willvary depending upon the host treated and the particular mode ofadministration. It will be understood, however, that the specific doselevel for any particular patient will depend upon a variety of factorsincluding the activity of the specific compound(s) employed, the age,body weight, general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

In all of the methods of the invention, appropriate dosages of theactive agent(s) can readily be determined by those of ordinary skill inthe art of medicine by monitoring the patient for signs of diseaseamelioration or inhibition, and increasing or decreasing the dosageand/or frequency of treatment as desired.

In various embodiments an amount equivalent to a dosage of about 10 mgto about 50 g/day, more preferably about 10 mg to about 10 g/day isadministered to a patient in need of such treatment. For example, thedosage can be in an amount of 10 mg, 50 mg, 100 mg, 200 mg, 300 mg, suchas 150 to 300 mg (e.g., 175 mg, 200 mg, 225 mg, or 250 mg).

Generally, treatment continues for at least one week and can continuefor several years or life-long as needed to control the subject'ssymptoms.

Administration and Formulations.

In various embodiments the pharmaceutical compositions can beadministered to the subject (e.g., patient) by any, or a combination, ofseveral routes, such as oral, intravenous, trans-mucosal (e.g., nasal,vaginal, etc.), pulmonary, transdermal, transnasal, ocular, buccal,sublingual, intraperitoneal, intrathecal, intramuscular, or long termdepot preparation. In certain embodiments solid compositions for oraladministration can contain suitable carriers or excipients, such as cornstarch, gelatin, lactose, acacia, sucrose, microcrystalline cellulose,kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodiumchloride, lipids, alginic acid, or ingredients for controlled slowrelease. Disintegrators that can be used include, without limitation,micro-crystalline cellulose, corn starch, sodium starch glycolate andalginic acid. Tablet binders that can be used include, withoutlimitation, acacia, methylcellulose, sodium carboxymethylcellulose,polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose,starch, and ethylcellulose.

In various embodiments liquid compositions for oral administrationprepared in water or other aqueous vehicles can include solutions,emulsions, syrups, and elixirs containing, together with the activecompound(s), wetting agents, sweeteners, coloring agents, and flavoringagents. Various liquid and powder compositions can be prepared byconventional methods for inhalation into the lungs of the patient to betreated.

In certain embodiments injectable compositions can contain variouscarriers such as vegetable oils, dimethylacetamide, dimethylformamide,ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, polyols(glycerol, propylene glycol, liquid polyethylene glycol, and the like).For intravenous injections, the compounds may be administered by thedrip method, whereby a pharmaceutical composition containing the activecompound(s) and a physiologically acceptable excipient is infused.Physiologically acceptable excipients may include, for example, 5%dextrose, 0.9% saline, Ringer's solution or other suitable excipients.For intramuscular preparations, a sterile composition of a suitablesoluble salt form of the compound can be dissolved and administered in apharmaceutical excipient such as Water-for-Injection, 0.9% saline, or 5%glucose solution, or depot forms of the compounds (e.g., decanoate,palmitate, undecylenic, enanthate) can be dissolved in sesame oil.Alternatively, the pharmaceutical composition can be formulated as achewing gum, lollipop, or the like.

In various embodiments combined formulations are contemplated. Incertain embodiments such formulations contain at least two of thefollowing three active agent(s): (i) an NMDA(N-methyl-D-aspartate)-Enhancer, and/or (ii) a glycine transporterinhibitor, and/or (iii) a D-amino Acid Oxidase Inhibitor (DAAOI). Incertain embodiments all three active agent(s) are present in a singleformulation. In combined formulations the different components can besegregated, for example, in different layers of a tablet, in differentmicrobeads/microcapsules, and the like. In certain embodiments two ofmore of the active agents are intermixed and/or suspended, e.g., in asingle excipient. Typically the different active agent(s) will beprovided each in a therapeutically effective dose.

D-Amino Acid Oxidase Inhibitor (DAAOI)

Many D-amino Acid Oxidase Inhibitors (DAAOIs) suitable for use in themethods of the present invention are well known to those of skill in theart. Suitable DAAO inhibitors include, for example, but are not limitedto benzoic acid and derivatives, sorbic acid and derivatives,2-oxo-3-pentynoate; Aminoguanidine (Guanylhydrazine; Carbamimidichydrazide; Pimagedine; GER 11; Hydrazinecarboximidamide) orhydrochloride salt (Guanylhydrazine hydrochloride), bicarbonate salt,nitrate salt, sulfate (2:1) salt, sulfate (1:1) salt, and hemisulfatesalt thereof; benzoic acid; sodium benzoate; 2-aminobenzoate;3-aminobenzoate; 4-aminobenzoate (p-aminobenzoate, PABA, Vitamin Bx,Vitamin H1); Methylglyoxal bis(guanylhydrazone) (also known as: MethylGAG; Mitoguazone; 1,114(methylethanediylidene)dinitrilo)diguanidine;Hydrazinecarboximidamide, 2,2′-(1-methyl-1,2-ethanediylidene)bis-;Pyruvaldehyde bis(amidinohydrazone); Megag; Mitoguazona [INN-Spanish];Guanidine, 1,1¹-((methylethanediylidene)dinitrilo)di-;1,1¹-((Methylethanediylidene)dinitrilo)diguanidine); Methylglyoxalbis(guanylhydrazone), dihydrochloride; phenylglyoxalbis(guanylhydrazone) (PhGBG); glyoxal bis(guanylhydrazone) (GBG;Guanidine, 1,11-(ethanediylidenedinitrilo)di(8C1);Hydrazinecarboximidamide, 2,2′-(1,2-ethanediylidene)bis-(9C1));indole-propionic (IPA, 3-(3-Indolyl)propanoic acid); 3-indole-aceticacid (Heteroauxin, IAA); Indole-3-acetic acid Sodium salt;Indole-3-acetone; Indole-3-acetamide; Indole-3-acetyl-L-aspartic acid;Indole-3-acetyl-L-alanine; Indole-3-acetylglycine; Indole-3-acetaldehydeSodium Bisulfite Addition compound; Indole-3-carboxylic acid;Indole-3-pyruvic acid (3-(3-Indolyl)-2-oxopropanoic acid); salicylicacid (2-Hydroxybenzoic acid); salicylic acid Sodium Salt; Salicylic acidPotassium Salt; Dansyl chloride (5-(Dimethylamino)naphthalene-1-sulfonylchloride); Dansyl fluoride (5-(Dimethylamino)naphthalene-1-sulfonylfluoride); dansyl glycine; Alanine tetrazole; benzoic tetrazole;tetrazole; Riboflavin 5′-pyrophosphate (RPP, 5-Phospho-alpha-D-ribosyldiphosphate, PRib-PP, P-RPP); DL-propargylglycine (DL-PG,2-Amino-4-pentynoic acid); L-C-Propargylglycine;N-Acetyl-DL-propargylglycine; (±)-Sodium 3-hydroxybutyrate; TrigonellineHydrochloride (1-Methylpyridinium-3-carboxylate); N-methylnicotinate;Methyl 6-methylnicotinate; Ethyl 2-methylnicotinate; Kojic acid(2-Hydroxymethyl-5-hydroxy-gamma-pyrone,5-Hydroxy-2-hydroxymethyl-4-pyranone); derivatives of kojic acid, suchas: 6-(pyrrolidinomethyl)-kojic acid hydrochloride,6-(morpholinomethyl)-kojic acid, 6-(diethylaminomethyl)-kojic acidhydrochloride; O-(2,4-dinitrophenyl)hydroxylamine; 2,4-dinitrophenylglycine; Hydroxylamine Hydrochloride; Methyl-p-nitrobenzenesulfonate(Methyl 4-nitrobenzenesulfonate); Aminoethylcysteine-ketimine (AECK,Thialysine ketimine, 2H-1,4-Thiazine-5,6-dihydro-3-carboxylic acid,S-Aminoethyl-L-cysteine ketimine, 2H-1,4-Thiazine-3-carboxylic acid,5,6-dihydro-); 1,4-thiazine derivatives; 4-Phenyl-1,4-sulfonazan(Tetrahydro-4-phenyl-4H-1,4-thiazine 1-oxide, 4H-1,4-Thiazine,tetrahydro-4-phenyl-, 1-oxide); 1. Phenothiazine (Thiodiphenylamine,10H-Phenothiazine, AFI-Tiazin, Agrazine, Antiverm,Dibenzo-1,4-thiazine); 3,4-Dihydro-2H-1,4-thiazine-3,5-dicarboxylic acid(3,4-Dhtca, CAS#86360-62-5); Nifurtimox (Nifurtimox [BAN:INN],1-((5-Nitrofurfurylidene)amino)-2-methyltetrahydro-1,4-thiazine-4,4-dioxide,3-Methyl-4-(5¹-nitrofurylidene-amino)-tetrahydro-4H-1,4-thiazine-1,1-dioxide,BAY 2502, 4-((5-Nitrofurfurylidene)amino)-3-methylthiomorpholine1,1-dioxide);3-(1-Pyrrolidinylmethyl)-4-(5,6-dichloro-1-indancarbonyl)-tetrahydro-1,4-thiazinehydrochloride (R 84760; R 84761; Thiomorpholine,4-((5,6-dichloro-2,3-dihydro-1Hinden-1-yl)carbonyl)-3-(1-pyrrolidinylmethyl)-,monohydrochloride, (R—(R*,S*))—); ketimine reduced forms; cystathionine;cystathionine ketimine; lanthionine ketimine;thiomorpholine-2-carboxylic acid; thiomorpholine-2,6-dicarboxylic acid;TMDA (1,4-Thiomorpholine-3,5-dicarboxylic acid); 1-chloro-1-nitroethane;anthranilate; Ethyl 2-aminobenzoate (ethyl anthranilate); Methyl2-aminobenzoate (Methyl anthranilate); picolinate; Ethyl picolinate(2-(Ethoxycarbonyl)pyridine, Ethyl 2-pyridinecarboxylate, L-Leucinemethyl ester, hydrochloride; L-leucine ([(S)-(+)-leucine]);Fluorodinitrobenzene (1-Fluoro-2,4-dinitrobenzene, 2,4-DNFB, Benzene,1-fluoro2,4-dinitro-, VAN); Dinitrochlorobenzene(1-Chloro-2,4-dinitrobenzene, 1,3-Dinitro-4-chlorobenzene);1,2-cyclohexanedione; Allylglycine (D-Allylglycine, 4-Pentenoic acid,2-amino-); 2-amino-2,4-pentadienoate; 2-hydroxy-2,4-pentadienoate;2-amino-4-keto-2-pentenoate; 2-hydroxybutyrate; Sodium2-hydroxybutyrate; N-chloro-D-leucine; N-Acetyl-D-leucine; D-Leu(D-2-Amino-4-methylpentanoic acid); D-propargylglycine;2-Amino-4-pentynoic acid; D,L-Propargylglycine; L-2-Amino4-pentynoicacid; Progesterone (4-Pregnene-3,20-dione); FAD (Flavin adeninedinucleotide, 1H-Purin-6-amine, flavin dinucleotide, Adenosine5′-(trihydrogen pyrophosphate), 5′-5′-ester with riboflavin); 6-OH-FAD;Phenylglyoxal (2,2-Dihydroxyacetophenone); Phenylglyoxal Monohydrate(2,2-Dihydroxyacetophenone monohydrate); Cyclothionine(Perhydro-1,4-thiazepine-3,5-dicarboxylic acid,1,4-Hexahydrothiazepine-3,5-dicarboxylic acid,1,4-Thiazepine-3,5-dicarboxylic acid, hexahydro-);alpha-alpha′-iminodipropionic (Alanopine; 2,21-Iminodipropionic acid;L-Alanine, N-(1-carboxyethyl)-); Meso-Diaminosuccinic acid(3-Aminoaspartic acid; Diaminosuccinic acid; CAS RN: 921-52-8);meso-2,3-Diaminosuccinic acid (CAS RN: 23220-52-2); Thiosemicarbazide(thiocarbamoyl hydrazide); Thiourea (Sulfourea; Thiocarbamide);Methylthiouracil (4(6)-Methyl-2-thiouracil, 4-Hydroxy-2-mercapto6-methylpyrimidine); Sulphathiazole (N1-(2-Thiazolypsulfanilamide,4-Amino-N-2-thiazolylbenzenesulfonamide); Sulfathiazole Sodium Salt(4-Amino-N-2-thiazolylbenzenesulfonamide sodium salt); thiocyanate;3-methylbenzyl thiocyanate; methimazole (2-mercapto-1-methylimidazole,1-methylimidazole-2-thiol); dicarboxylic hydroxyacids;1,3-Acetonedicarboxylic acid (3-Oxoglutaric acid); D-tartaric acid([(25,35)-(−)-tartaric acid, unnatural tartaric acid]); L-tartaric acid([(2R,3R)-(+)-tartaric acid, natural tartaric acid]); DL-tartaric acid;potassium tartrate; D-malic acid; [(R)-(+)-malic acid,(R)-(+)-hydroxysuccinic acid]; L-malic acid; [(S)-(−)-malic acid,(S)-(−)-hydroxysuccinic acid]; DL-Malic acid (DL-hydroxysuccinic acid);Alpha-keto acids that are analogues of the amino acids alanine, leucine,phenylanaline, phenylglycine, tyrosine, serine, aspartate, and salts andderivatives thereof; pyruvic acid (2-Oxopropionic acid,alpha-Ketopropionic acid); sodium pyruvate; Pyruvic acid methyl ester(methyl pyruvate); Phenylpyruvic acid; Calcium phenylpyruvate (calciumpyruvate); Phenylpyruvic acid Sodium salt (Sodium phenylpyruvate);4-hydroxyphenyl pyruvic acid; sodium alpha-ketoisovaleric acid(3-Methyl-2-oxobutyric acid sodium salt, 3-methyl-2-oxobutanoic acidsodium salt, (α-Ketoisovaleric acid Sodium salt; Ketovaline Sodiumsalt); benzoylformic acid (α-Oxophenylacetic acid, Phenylglyoxylicacid); 4-methylthio-2-oxopentanoic acid; 4-Methyl-2-oxopentanoic acid(4-Methyl-2-oxovaleric acid; alpha-Ketoisocaproic acid;4-methylthio-2-oxybutanoic acid; 2-oxybutanoic acid (hydroxybutyrate;2-Hydroxybutyric acid; alpha-Hydroxy-n-butyric acid;DL-alpha-Hydroxybutyric acid Sodium Salt (sodium (±)-2-Hydroxybutyrate);Indole-3-pyruvic acid (alpha-Keto analogue of tryptophan); The reactionproduct between cysteamine and bromopyruvate; cysteamine(2-Aminoethanethiol; 2-Mercaptoethylamine); pantetheine;5-adenosylmethionine; Ethyl bromopyruvate; Methyl bromopyruvate;Bromopyruvate; and 5-S-Cysteinyldopamine (see, e.g., PCT Publication WO03/047558 and US Patent Publication No: 2003/0185754 A1).

Benzoic and Sorbic Acid Salts and Derivatives.

In certain embodiments preferred DAAOIs include, but are not limited toa benzoic acid, benzoic acid salt, benzoic acid ester and/or aderivative thereof, and/or sorbic acid, a sorbic acid salt, or aderivative thereof. Illustrative benzoic acid salts include, but are notlimited to sodium benzoate, potassium benzoate, calcium benzoate,lithium benzoate, magnesium benzoate, zinc benzoate, and the like. Incertain embodiments the benzoate is selected from the group consistingof benzoic acid; sodium benzoate; 2-aminobenzoate; 3-aminobenzoate;4-aminobenzoate (p-aminobenzoate, PABA, Vitamin Bx, Vitamin H1, andbenzo[d]isoxazol-3-ol derivatives (see, e.g., U.S. Pat. No. 7,166,725,PCT Publication WO 03/047558, and US Patent Publication No: 2003/0185754A1 which are incorporated herein by reference), and the like. In certainembodiments the compounds discloses in U.S. Pat. No. 7,166,725, PCTPublication WO 03/047558, and US Patent Publication No: 2003/0185754 A1are expressly excluded.

Illustrative sorbic acid (2,4-hexadienoic acid) salts include, but arenot limited to sodium sorbate, potassium sorbate, calcium sorbate. Othersorbic acid derivatives include, but are not limited to sorbohydroxamicacid, sorbic aldehyde, sorbic acid-thiol adducts, 8-quinolinylsorbate,m-nitrosorbanilide, and the like.

NMDA Enhancer

NMDA enhancers suitable for use in certain methods of the presentinvention are well known to those of skill in the art. Suitable NMDAenhancers include, for example, but are not limited to D-alanine, a saltof D-alanine, an ester of D-alanine, an alkylated D-alanine, a precursorof D-alanine, D-serine, a salt of D-serine, an alkylated D-serine, aprecursor of D-serine, D-cycloserine, a salt of D-cycloserine, an esterof D-cycloserine, a precursor of D-cycloserine, an alkylatedD-cycloserine, N,N-dimethylglycine, a salt of N,N-dimethylglycine, anester of N,N-dimethylglycine, an alkylated N,N-dimethylglycine, andN,N,N-trimethylglycine.

In certain embodiments the composition is substantially free ofD-cycloserine when the agonist is D-alanine, a salt of D-alanine, anester of D-alanine, an alkylated D-alanine, or a precursor of D-alanine;and when the agonist is D-cycloserine, a salt of D-cycloserine, an esterof D-cycloserine, a precursor of D-cycloserine, or alkylatedD-cycloserine, the pharmaceutical composition comprises an amount of theagonist equivalent to 105-500 mg of D-cycloserine.

Glycine Transporter Inhibitor.

Glycine transporter inhibitors suitable for use in the methods of thepresent invention are well known to those of skill in the art. Suitableglycine transporter inhibitors include, but are not limited to sarcosine(N-methyl glycine),N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine,(+)N[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine (NFPS),pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl piperidine compounds(see, e.g., WO/2005/094514, which is incorporated herein by reference,Pinard et al. (2008) Bioorg Med Chem Lett. 18(18): 5134-5139; Boulay etal. 92008) Pharmacol Biochem Behav. 91(1):47-58; Lindsley et al. (2006)Curr Top Med Chem. 6(17): 1883-1896; Depoortbre et al. (2005)Neuropsychopharmacology 30(11): 1963-1985; Brown et al. (2001) BioorgMed Chem Lett. 11(15): 2007-2009). Other glycine transporter inhibitorsinclude, but are not limited toN-{3-[5-Cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}glycineethyl ester,N-{3-[5-Cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycineethyl ester,N-{3-[5-Cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}glycine,N-{3-[5-Cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-{3-[1-(3-chlorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-{3-[1-(3-trifluoromethylphenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-{3-[1-(3-trifluoromethylphenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methyl(1-ethyl)glycine,N-{3-[1-(4-methylphenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-{3-[1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-{3-[1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylalanine,N-{3-[1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methyl(1-ethyl)glycine,N-{3-[4-chloro-1-(3-methyl-4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-{3-[4-chloro-1-(4-chlorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-{3-[5-chloro-1-(4-chlorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylalanine,N-{3-[6-chloro-1-(3-methyl-4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-{3-[6-chloro-1-(4-chlorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-{(3-[6-chloro-1-(4-methylphenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-{3-[6-chloro-1-(4-methoxyphenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-{3-[5-fluoro-1-(4-chlorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-{3-[5-fluoro-1-(4-methoxyphenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-{3-[5-trifluoromethyl-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-{3-[5-trifluoromethyl-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylalanine,N-{3-[5-cyano-1-(3-methyl-4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-{3-[5-cyano-1-(4-cyanophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylalanine,N-{3-[5-cyano-1-(4-methoxyphenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-{3-[5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-{2-[5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]ethyl}-N-methylglycine,N-{3-[5-Chloro-1-(4-chloro-phenyl)-indan-1-yl]-propyl}-N-methylglycine,N-{3-[5-Chloro-1-(4-chloro-phenyl)-indan-1-yl]-propyl}-N-methylalanine,N-{3-[3-cyclo-1-(4-methylphenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-[3-(3,3-Dimethyl-1-phenyl-1,3-dihydro-benzo[c]thiophen-1-yl)-propyl]-N-methylglycine,N-[3-(3,3-Dimethyl-1-phenyl-1,3-dihydro-benzo[c]thiophen-1-yl)-propyl]-N-methylalanine,N-{3-[1-(4-Fluoro-phenyl)-3-dimethyl-1,3-dihydro-isobenzofuran-1-yl]-propyl}-Nmethylglycine,N-{3-[5-Bromo-1-(4-chlorophenyl)-1,3-dihydroisobenzofuran-1-yl]-1-propyl}-N-methylglycine,N-{2-[1-(4-Chloro-phenyl)-3,3-dimethyl-1,3-dihydro-isobenzofuran-1-yl]-ethyl}-N-methylglycine,N-[3-(3-methyl-1-phenyl-1H-inden-1-yl)-propyl]-N-methylglycine,N-[3-(5-Chloro-1-thiophen-2-yl-1,3-dihydro-isobenzofuran-1-yl)-propyl]-N-methylglycine,N-[3-(5-Chloro-1-thiophen-2-yl-1,3-dihydro-isobenzofuran-1-yl)-propyl]-N-methyl(1-ethyl)-glycine,N-[3-(3-methyl-1-phenyl-1,3-dihydro-isobenzofuran-1-yl)-propyl]-N-methylalanine,N-[3-(3-methyl-1-phenyl-1,3-dihydro-isobenzofuran-1-yl)-propyl]-N-methyl(1-ethyl)-glycine,N-[3-(3,3-Dimethyl-1-phenyl-1,3-dihydro-isobenzofuran-1-yl)-ethyl]-N-methylalanine,N-[3-(3,3-Dimethyl-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-1-yl)-ethyl]-N-methylalanine,N-[3-(3,3-Dimethyl-1-phenyl-1,3-dihydro-isobenzofuran-1-yl)-ethyl]-N-methyl-(1-ethyl)glycine,N-[3-(3,3-Dimethyl-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-1-yl)-ethyl]-N-methyl-(1-ethyl)glycine,N-[3-(3,3-Diethyl-1-phenyl-1,3-dihydro-isobenzofuran-1-yl)-propyl]-N-methylalanine,N-[3-(3,3-Diethyl-1-(4-chloro-phenyl)-1,3-dihydro-isobenzofuran-1-yl)-propyl]-N-methylalanine,N-[3-(3,3-Diethyl-1-(4-chloro-phenyl)-1,3-dihydro-isobenzofuran-1-yl)-propyl]-N-methylglycine,N-[3-(1-phenyl-1,3-dihydro-benzo[c]thiophen-1-yl)-propyl]-N-methylalanine,N-{3-[1-(4-Chloro-phenyl)-3,3-dimethyl-indan-1-yl]-propyl}-N-methylglycine,N-{3-[1-(4-Chloro-phenyl)-3,3-diethyl-1,3-dihydro-isobenzofuran-1-yl]-propyl}-N-methyl-alanine,N-[2-(3-methyl-1-phenyl-indan-1-yl)-ethyl]-amino}-N-methylalanine,N-[3-(1-phenyl-(1H)-inden-1-yl)-propyl]-N-methylalanine,N-{3-[1-(4-Fluoro-phenyl)-5-(4-trifluoromethyl-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-propyl}-N-methyl-glycine,N-{3-[5-Chloro-1-(4-chloro-phenyl)-indan-1-yl]-propyl}-N-methyl-glycine,N-{3-[5-Chloro-1-(4-chloro-phenyl)-indan-1-yl]-propyl}-N-methyl-alanine,N-{3-[1-(4-chloro-phenyl)-5-(4-trifluoromethyl-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-ethyl}-N-methyl-glycine,N-{3-[1-(4-Chloro-phenyl)-5-(4-methyl-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-ethyl}-N-methyl-glycine,N-{3-[1-(4-Chloro-phenyl)-5-(4-methoxy-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-ethyl}-N-methyl-glycine,N-{3-[1-(4-Chloro-phenyl)-5-(2-thiophenyl)-1,3-dihydro-isobenzofuran-1-yl]-ethyl}-N-methyl-glycine,N-{3-[1-(4-Chloro-phenyl)-5-(4-methyl-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-propyl}-N-methyl-glycine,N-{3-[1-(4-Chloro-phenyl)-5-(4-methoxy-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-propyl}-N-methyl-glycine,N-{3-[1-(4-chloro-phenyl)-5-(4-trifluoromethyl-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-propyl}-N-methyl-glycine,N-{3-[1-(4-Chloro-phenyl)-5-(4-chloro-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-ethyl}-N-methyl-glycine,N-{2-[1-(4-Chloro-phenyl)-5-(5-chloro-thiophen-2-yl)-1,3-dihydro-isobenzofuran-1-yl]-ethyl}-N-methyl-glycine,N-{3-[1-(4-Chloro-phenyl)-5-(3-methyl-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-ethyl}-N-methyl-glycine,N-{3-[1-(4-Chloro-phenyl)-5-(2-methyl-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-ethyl}-N-methyl-glycine,N-{3-[1-(4-Chloro-phenyl)-5-(2,5-dichloro-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-ethyl}-N-methyl-glycine,N-{3-[1-(4-chloro-phenyl)-5-(3-trifluoromethyl-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-ethyl}-N-methyl-glycine,N-{3-[1-(4-chloro-phenyl)-5-(3-trifluoromethyl-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-propyl}-N-methyl-glycine,N-{3-[1-(4-Chloro-phenyl)-5-(3,4-dichloro-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-ethyl}-N-methyl-glycine,N-{3-[1-(4-Chloro-phenyl)-5-(4-chloro-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-propyl}-N-methyl-glycine,N-{3-[1-(4-Chloro-phenyl)-5-(3-methyl-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-propyl}-N-methyl-glycine,N-{3-[1-(4-Chloro-phenyl)-5-(2-methyl-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-propyl}-N-methyl-glycine,N-{3-[1-(4-Chloro-phenyl)-5-(2,5-dichloro-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-propyl}-N-methyl-glycine,N-{3-[1-(4-Chloro-phenyl)-5-(3,4-dichloro-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-propyl}-N-methyl-glycine,andN-{3-[1-(4-chloro-phenyl)-5-(2-trifluoromethyl-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-propyl}-N-methyl-glycine(see, e.g., U.S. Pat. No. 6,921,774, which is incorporated herein byreference), or other non glycine-, N-methylglycine-structurally basedinhibitors (see, e.g., Harsing et al. (2006) Current MedicinalChemistry, 13: 1017-1104).

Additional Active Agents.

In certain embodiments the methods can involve administering additionalneuropharmaceuticals and other therapeutic agents instead of or inconjunction with the agents described above.

In certain embodiments such agents include, but are not limited todiazepam, bromazepam, prazepam, Chlordiazepoxide, Clobazam, Estazolam,Flurazepam, Clonazepam, Temazepam, Triazolam, Alprazolam, Midazolam,Brotizolam, Nitrazepam, Flunitrazepam, Oxazepam, Quazepam, Lorazepam,Temazepam, Triazolam, Zolpidem, Zopiclone, Zaleplon, Chlorpromazine,Thioridazine, Mesoridazine, Fluphenazine, Perphenazine, Trifluoperazine,Thiothixene, Haloperidol, Loxapine, Molindone, Clozapine, Risperidone,Olanzapine, Quetiapine, Haloperidol decanoate, Fluphenazine decanoate,Fluphenazine enanthate, Risperdal Consta, Amitriptyline, Amoxapine,Bupropion, Bupropion SR, Citalopram, S-Citalopram, Clomipramine,Desipramine, Doxepin, Duloxetine, Milnacipran, Fluoxetine, Fluvoxamine,Imipramine, Isocarboxazid, Lamatrogine, Lithium, Topiramate, Gabapentin,Carbamazepine, Oxacarbazepine, Valporate, Maprotiline, Memantine,Mirtazapine, Brofaromine, Gepirone, Moclobemide, Physostigmine,Nicotine, Huperzine Alpha, vitamin C, vitamin E, Carotenoids, GinkgoBiloba, Statins, Nefazodone, Nortriptyline, Paroxetine, Phenelzine,Protriptyline, Sertraline, Protriptyline, Trimipramine, Amoxapine,isoniazid, iproniazid, venlafaxine, Velafaxine XR, mianserin,reboxetine, Selegiline, Tranylcypromine, Trazodone, Trimipramine,Venlafaxine, Velafaxine XR, Amphetamine, Modafinil, Desoxyn,Methamphetamine, arecoline, Dexmethylphenidate (Focalin, Focalin XR),dextroamphetamine (Dexedrine, Dexedrine Spansules, Dextroamphetamine ER,Dextrostat), methylphenidate (Concerta, Daytrana, Metadate CD, MetadateER, Methylin, Methylin ER, Ritalin, Ritalin-LA, Ritalin-SR),lisdexamfetamine dimesylate (Vyvanse), mixed salts amphetamine(Adderall, Adderall XR), Atomoxetine (Strattera), clonidinehydrochloride (Catapres), guanfacine hydrochloride (Tenex), cocaine,Pemoline, Donepezil, Tacrine, Rivastigmine, Acetophenazine,Chlorprothixene, Droperidol, Pimozide, Butaperazine, Carphenazine,Remoxipride, Piperacetazine, Sulpiride, Ziprasidone, aripiprazole,Paliperidone, lamotrigine (LAMICTAL®), memantine (AXURA®, AKATINOL®,NAMENDA®, EBIXA®, ABIXA®), arecoline, acamprosate, tetrabenazine(XENAZINE®, NITOMAN®), RILUTEK® (riluzole), and the like.

Compound Formulations.

In certain embodiments, the agents described herein (e.g., benzoic acid,benzoic acid salt, or derivative thereof and/or sorbic acid, sorbic acidsalt, or derivative thereof) and a neuropharmaceutical (e.g., asdescribed herein) are administered separately, either simultaneously orsequentially. The agents are commercially available in suitablepharmaceutically acceptable formulations.

In certain embodiments, however, the agents e.g., benzoic acid, benzoicacid salt, benzoic acid ester, or other benzoic acid derivative and/orsorbic acid, sorbic acid salt, sorbic acid ester, or other sorbic acidderivative, and neuropharmaceutical (e.g., antidepressant,antipsychotic, phsychostimulant, mood stablizers, anxiolytic, ADHDtherapeutic, Alzheimer's disease therapeutic, and other psychotropicsetc.) are provided as a combined formulations for administration by anyof a variety of modalities including, but not limited to oraladministration, rectal administration, injection, transdermaladministration, subcutaneous depot administration, transnasaladministration, and the like. Methods of preparing combined formulationsare well known to those of skill in the art (see, e.g., Remington'sPharmaceutical Science, 15th ed., Mack Publishing Company, Easton, Pa.(1980), Remington: The Science and Practice of Pharmacy, 21st Ed. 2005,Lippincott Williams & Wilkins, and the like).

For example, for oral administration, the active agent(s) (e.g., benzoicacid, salt or derivative, and/or sorbic acid, salt, or derivative, andantipsychotic) can be combined with one or more excipients and used inthe form of ingestible tablets, buccal tablets, troches, capsules,elixirs, suspensions, syrups, wafers, and the like. In waferformulations, for example, different layers comprising the wafer cancontain different agents. Similarly time-release capsules can comprisemultiple active agents. Such compositions and preparations are typicallyformulated to deliver the desired concentration of agent(s) over thedesired time period.

Similarly, for injectables, the active agents can be combined into asingle injectable formulation.

Kits

In another embodiment this invention provides kits treating (e.g.,mitigating one or more symptoms of) a neuropsychiatric disorder. Thekits preferably comprise a container or containers containing thecombinations of active agents described herein, either a separateformulations or as a single “combined” formulation. The agent(s) can beprovided in a unit dosage formulation (e.g. suppository, tablet, caplet,patch, etc.) and/or may be optionally combined with one or morepharmaceutically acceptable excipients.

In certain embodiments the kits comprise benzoic acid, a benzoic acidsalt, or a derivative thereof and/or sorbic acid, a sorbic acid salt, ora derivative thereof, and a neuropharmaceutical (e.g., anantipsychotic). The agents can be in separate containers or in the samecontainer.

In addition, the kits optionally include labeling and/or instructionalmaterials providing directions (i.e., protocols) for the practice of themethods or use of the “therapeutics” or “prophylactics” of thisinvention. Preferred instructional materials describe the use ofcombinations of agents as described herein to mitigate symptom(s) of aneuropsychiatric disorder and/or to prevent the onset or increase of oneor more of such symptoms in an individual at risk for such a disorder.The instructional materials can also, optionally, teach preferreddosages/therapeutic regiment, counter indications and the like.

While the instructional materials typically comprise written or printedmaterials they are not limited to such. Any medium capable of storingsuch instructions and communicating them to an end user is contemplatedby this invention. Such media include, but are not limited to electronicstorage media (e.g., magnetic discs, tapes, cartridges, chips), opticalmedia (e.g., CD ROM), and the like. Such media may include addresses tointernet sites that provide such instructional materials.

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed invention.

Example 1

Introduction

Treatment by the agents enhancing N-methyl-D-aspartate neurotransmissionhave gained attention as an alternative for patients not responding toavailable psychotropics including antipsychotic medication. However, theefficacy of the individual NMDA-enhancement is limited at typicaldosages. We believe a combination of NMDA-enhancing agents will renderbetter clinical efficacy than an individual agent alone. To evaluatethis hypothesis, we applied the combinational strategy in the bestaccepted neurophysiological model of schizophrenia in rodents, startlehabituation and prepulse inhibition (PPI).

The startle response is comprised of a constellation of reflexeselicited by sudden relatively intense stimuli. It offers many advantagesas a behavioral measure of central nervous system activity when elicitedby acoustic (noise burst), electrical (cutaneous), tactile (air puff),or visual (light flash) stimuli. The startle reflex has served as a toolfor studying fundamental properties of nervous function of complexbehavioral states and cognitive processes.

The forebrain modulates several forms of startle plasticity includingthe habituation and PPI. Changes in startle magnitude through repeatedstimulus presentations-habituation and sensitization-represent thesimple forms of learning. Quantification of startle habituation andsensitization in rodent has direct physiological relevance to human CNSfunction. In fact, the most well accepted animal physiology models forschizophrenia are startle habituation and PPI.

Therefore, to test the hypothesis that combinational NMDA-enhancingagent treatment has better efficacy than individual agent alone, wetested startle habituation and PPI in animals receiving singleNMDA-enhancing agents, sarcosine (N-methylglycine, a glycinetransporter-1 inhibitor), benzoate (a D-amino acid oxidase inhibitor),the combination of both agents or the vehicle. We also tested thehypothesis in a well accepted pharmacological model of schizophrenia,amphetamine-disruption of startle habituation and PPI.

Method

For the systematic investigation of the neurobiological systems thatmodulate sensorimotor inhibition, startle magnitude was investigated.Startle magnitude is reduced when the pulse stimulus is preceded 30 to500 msec by a weak prepulse. This inhibition (“gating”) of a motorresponse elicited by a weak sensory event, termed PPI, provides anoperational measure of sensorimotor gating. Prepulse stimuli of 3, 6, or12 dB above the 70 dB background noise inhibit the startle responseelicited by 120-dB pulse stimuli. Prestimuli used in intramodal studiesof sensorimotor gating of acoustic startle are by the delivery of adiscrete acoustic prepulse several msec before the startle pulse, withan intensity below startle threshold. Holding the interval between theprepulse and pulse stimuli constant at 100 msec typically yieldssuitable levels of PPI, ranging from 20% to 80% inhibition.

For habituation, we present six trials of a single acoustic stimulus toeach mouse. To provide a consistent acoustic environment and to maskexternal noises, maintain a continuous background noise level of 70 dBwithin each startle chamber. We collected the peak or average responsefrom each mouse on each of six trials, then averaged the six responsestogether for each mouse. Five more trials at the end of PPI were done.The results were averaged and compared to the original six trials. Thedifference of startle responses between the initial six and the lastfive trials were considered the amount of habituation. Analyses includethe independent variable (e.g., vehicle or drug treatment) as a factorin analyses of variance (ANOVA) on the dependent measures (difference ofthe average of the first and last six trials).

There were a total of 36 trials in the experiments. The three prepulsestimuli were with a duration of 20 msec. For each mouse the followingmetrics were determined: 1) Average response magnitude on pulse-onlytrials 1 to 6 and 32 to 36; 2) Average response magnitude in each of thefour trial types between trials 7 and 31 inclusively (i.e., tenpulse-only trials and five each of the three prepulse variations). Thefirst block of pulse-only trials were analyzed as measures of startlereactivity. The first and last blocks of pulse-only trials were analyzedtogether in a repeated measure ANOVA to assess habituation of acousticstartle across the test session. The four values (3, 6, or 12 dB abovebackground) derived from trials 7 to 31 were used to assess PPI whichwas calculated for each mouse as: Percentage score:PPI=100%×{[pulse-only units−(prepulse+pulse units)]/(pulse-only units)}.

Male 129 SVE adult mice were first tested at baseline. Four groups of 10mice each were treated with sarcosine (200 mg/kg), benzoate (100 mg/kg),a combination of both sarcosine and benzoate (same doses as theindividual treatment), or with vehicle for one week before the test. Themice continued to receive the drug until one week later whenamphetamatine (10 mg/kg) was administered 30 minutes before theexperiments.

Results

We found that there was no difference in the habituation at baseline(when no drug had been administered) across the groups (FIG. 1, leftgroup). But combination treatments induce a stronger habituation effectthan benzoate or sarcosine treatment alone (FIG. 1, middle group). Theeffect of benzoate, however, was close to the combination treatment. Thesame trend of habituation (combination treatment>benzoate>sarcosine) wasevident when amphetamine was administered and disrupted the habituation(FIG. 1, right group). The combination is better than the individualtreatment in enhancing the habituation (FIG. 1, middle). The combinationtreatment corrected the amphetamine-induced disruption of habituationback to normal state while single treatment of NMG or benzoate partiallycorrect the deficit (FIG. 1, right group). The effect of benzoate,however, is better than sarcosine and close to effect seen in thecombination treatment.

For PPI, we found that in general stronger prepulse inhibited pulseresponse more (inhibition of 525 Hz>487 Hz>468 Hz) (FIG. 2). Amphetaminedisrupted the inhibition in all treatments. This disruption byamphetamine is most pronounced in vehicle treated mice (left column),partially corrected by either sarcosine (NMG) or benzoate (middle 2columns) and was best corrected by the combination treatment (rightcolumn).

Conclusion

In the most accepted animal model of schizophrenia, which tests thesensory gating, we found that combination treatment improve the startlehabituation and PPI significantly more than the individual agent alone.The effect of benzoate was close to combination treatment inhabituation.

Example 2

Treatment of Schizophrenia by Sodium Benzoate, a D-Amino Acid OxidaseInhibitor

Schizophrenia is a devastating mental disorder with high morbidity andmortality, affecting about 1% of the population worldwide. Furthermore,care for schizophrenia is extremely expensive in terms of direct andindirect costs. Clinical manifestation of schizophrenia consists ofthree domains: positive symptoms, negative symptoms, andneuropsychological deficits that are poorly addressed today.

Therapeutic Need for Schizophrenia—Beyond Clozapine

Pharmacotherapy of schizophrenia has been developed for half century.Conventional antipsychotics, which blockade majority of D₂ dopaminereceptors only exerted effects on positive symptoms. Newer atypicalantipsychotics targeting both dopamine D₂ and serotonin 5HT₂ receptorshave been suggested to be superior to conventional agents in terms ofefficacy for positive symptoms, negative symptoms and cognitivedeficits. Despite this, there were a considerable percentage of patientsresistant or only partially responsive to available medications.Moreover, side-effect profiles of second-generation antipsychotic agentsare significant, including hypotension, seizure, sedation, weight gain,hyperglycemia, diabetes mellitus, hyperlipidemia, and hematologicalabnormalities, limit their clinical use. Lastly, most schizophrenicpatients still suffer from lifelong illness and deteriorating function.

Materials and Methods

Subjects

The research protocol was approved by the Institutional Review Boards(IRB) of the institute. Patients were screened and evaluated by theresearch psychiatrists. After complete description of the study to thesubjects, written informed consent was obtained in line with the IRB'sguidelines. The Structured Clinical Interview for DSM-IV was conductedfor the diagnosis. Patients entered into this study if they 1) werephysically healthy and had all laboratory assessments (includingurine/blood routine, biochemical tests, and electrocardiograph) withinnormal limits, 2) aged 18-60 years, 3) satisfied DSM-IV criteria forschizophrenia (2), 4) had no DSM-IV diagnosis of substance (includingalcohol) abuse or dependence, 5) consistently symptomatic withoutfluctuation and the antipsychotic doses were unchanged for at least 3months, and 6) had a minimum baseline total score of 60 on the Positiveand Negative Syndrome Scale (PANSS) (3).

Study Design

The dosing for the concurrent antipsychotics (all atypicalantipsychotics), was an optimal dosing strategy which minimize sideeffects, especially extrapyramidal side effects (EPS), and can stillyield favorable efficacy. After having achieved optimal treatmentresponse, patients' antipsychotic doses remained constant for at leastthree months prior to the enrollment of the study and remained on thesame antipsychotic regimens for the study period. All patients aretreated with atypical antipsychotics, risperidone in majority.

All patients were then randomly assigned under double-blind conditionsto receive a 6-week trial of placebo, or sodium benzoate (1 grams)daily. Patients were randomized in clusters of six subjects, withoutstratification, through a computer-generated randomization table toreceive placebo or active drugs in a 1:1 ratio. To ensure concealment ofthe randomization assignment, study medication was provided in codedcontainers with supply of identical-appearing capsules of placebo oreither of active compounds. The research pharmacist implemented randomallocation and masked treatment assignment was communicated by telephoneto research staff. Patients, caregivers, and investigators (except forthe investigational pharmacist) were all masked to the assignment.Patient's compliance and safety were closely monitored by the researchpsychiatrists and the inpatient nursing staff.

Measures

The primary outcome measures were psychopathology changes measured byPANSS (3) and, Scales for the Assessment of Negative symptoms (SANS) (4)total scores, Quality of Life scale (10 items for inpatient use) (1, 5),and Global Assessment of Function (Axis V in DSM IV) (2). A secondaryanalysis aimed to explore whether the positive results (if any) from thePANSS or SANS were due to a general effect on all components or to aneffect on a specific component(s).

Factor analyses for PANSS revealed 5 components: positive, negative,cognitive, depression and excitement (3). For the assessment of negativesymptoms, we a priori chose SANS rather than PANSS-negative to avoidmultiple comparisons because SANS is more comprehensive, consisted offive subscales: blunted affect, alogia, apathy, anhedonia/asociality,and attention (4). Nevertheless, we also presented the findings in thePANSS-negative component. Of the original 21 items on the Quality ofLife scale (5), 10 (social activity, social initiatives, socialwithdrawal, sense of purpose, motivation, curiosity, anhedonia, aimlessinactivity, capacity for empathy, emotional interaction) are selectedfor the inpatient setting (1). The Global Assessment of Function (GAF,Axis V in DSM IV) includes symptoms in the anchors (2). The GAF raterswere instructed to ignore the symptom components.

Side-effect assessments included Simpson-Angus Rating Scale for EPS (6),Abnormal Involuntary Movement Scale (AIMS) for dyskinesia (7), andBarnes Akathesia Scale (8). Systemic side effects of treatments wereevaluated by means of routine physical and neurological examinations,laboratory tests, and reviewed by applying the Udvalg for KliniskeUndersogelser (UKU) Side-effects Rating Scale (9).

Clinical ratings were performed by the research psychiatrists who weretrained and experienced in the rating scales. Inter-rater reliabilitywas analyzed with the ANOVA test. Only raters reaching the intraclasscorrelation coefficients of 0.90 or higher during pre-study trainingwere allowed to rate the study patients. To maintain high interraterreliability and to prevent rater drift, raters met at least once a monthfor training and reliability re-testing. To minimize interratervariability, individual patients were assessed by the same researchpsychiatrist throughout the trial. Assessments were completed atbaseline and at the end of weeks 2, 4, and 6.

Statistical Analysis

The demographic and clinical characteristics of the patients,antipsychotic doses, response rate, and side effects among groups werecompared by Kruskal Wallis tests (or ANOVA tests if the distribution wasnormal) for continuous variables and by Chi-Square tests (or Fisher'sExact tests) for categorical variables.

We applied multiple linear regression with the generalized estimatingequation (GEE) method (10) for the treatment by time (0, 2, 4, 6 weeks)interaction analysis, which simultaneously compared the treatment groupsusing a single analysis and allowed controlling for baselinepsychopathology. The results of GEE models were analyzed by the SAS/STAT(SAS Institute Inc, Cary, N.C.) “PROC GENMOD” procedure with AR(autoregressive) (1) working correlation structure using the marginalmodel. Since there are three comparison groups, the placebo group wasselected to be compared with the two active treatment groups. BecauseANOVA and multiple linear regression can be applied only if thedistribution of the response values is normal, we examined thedistribution pattern using the “Kolmogorov D” package in SAS/INSIGHTv8.2. All hypothesis tests were two sided and conducted at the 0.05alpha levels. To compare across the treatments, effect sizes betweenendpoint and baseline were calculated.

Results

In this pilot, placebo-control, randomized, double blind trial (not yetpublished), we found that 1000-mg/day sodium benzoate adjunctive therapy(n=18) can significantly improve positive and negative symptoms andquality of life than placebo (n=18) in schizophrenia patients (FIG. 3).Benzoate also yielded good safety and tolerability. Treatment-emergentside effects were also similar between benzoate and placebo groups.These side effects were all mild, short-lived, and not warrantingmedical treatment.

We had optimized the treatment of schizophrenia by reconfirming theefficacy and safety of risperidone (ris)-benzoate combination (RBC). Wefound RBC was superior to risperidone (ris) (placebo add on) in allclinical domains, including cognitive function and life quality and itssafety is equal to ris (placebo addon) treatment. This beneficialoutcome will provide a new treatment for schizophrenia and markedlyreduce the social cost for this severe mental disorder.

Example 3

Following acclimation at least 7 days in the animal facility prior toinitiation of behavioral testing, the animals (rats) were subjected tothe forced swim test (FST). The method of the FST has been used inprevious animal studies of depression, which was modified by Cryan fromthe Porsolt's FST. (Porsolt et al, 1977; Cryan et al, 2002) The test wasperformed using a acrylic cylinder (diameter, 20 cm; height, 40 cm)filled to a height of 30 cm with 25° C. water. Rats were processed to a15-min conditioning swim. Following 24 h after their first exposure, therats were again placed in the swim apparatus for 5 min. The behavior ofrats was observed 5 min after the administration of various drugtreatments or 0.9% saline (control). All behavioral testing wasconducted between 1600-1800 h. On the study day, the total periods ofimmobility during the 5-min testing period were recorded using theEthoVision Basic V 3.1 analysis program (Noldus, Wageningen,Netherlands). For the present experiment, the immobility threshold wasset at 15% and a fixed averaging interval of 1 second was chosen tosmooth the mobility parameter in EthoVision software. Below the immobilethreshold, the animal is considered immobile. Using the settings, theactivity of all rats was analyzed automatically and quantitatively formobility and numbers of crossing vertical central line in the FST.

TABLE 1 Treatment effects for sodium benzoate and potassium sorbate inforced swim test. Sodium Potassium Benzoate Sorbate Vehicle (500 mg/kg)(500 mg/kg) Immobility 46.94 ± 4.6 40.17 ± 3.3 27.64 ± 6.2 time (p <0.05) (p < 0.01) (%)

The table indicates the scores on the behavioral scales of FST in threetreatment groups. As can be seen, both sodium benzoate and potassiumsorbate decrease the duration of immobility significantly as compared tothe vehicle control group.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

What is claimed is:
 1. A method for alleviating a symptom of dementia ormild cognitive impairment, the method comprising: administering orallyto a subject in need thereof benzoic acid or a pharmaceuticallyacceptable salt thereof at an amount of 200 mg to 2000 mg per day. 2.The method of claim 1, wherein the subject has been treated with anacetylcholine esterase inhibitor.
 3. The method of claim 2, wherein theacetylcholine esterase inhibitor is tacrine, donepezil, or rivastigmine.4. The method of claim 1, wherein the subject is administered withbenzoic acid.
 5. The method of claim 1, wherein the subject isadministered with a pharmaceutical acceptable salt of benzoic acid,which is sodium benzoate, potassium benzoate, calcium benzoate, orlithium benzoate.
 6. The method of claim 5, wherein the subject isadministered with sodium benzoate.
 7. The method of claim 1, wherein thesubject is administered with benzoic acid or the pharmaceuticallyacceptable salt thereof at an amount of 300 mg to 2000 mg per day. 8.The method of claim 7, wherein the subject is administered with benzoicacid or the pharmaceutically acceptable salt thereof at an amount of 500mg to 2000 mg per day.
 9. A method for alleviating a symptom of dementiaor mild cognitive impairment, the method comprising: administering to asubject in need thereof benzoic acid or a pharmaceutically acceptablesalt thereof at an amount of 200 mg to 2000 mg per day and an effectiveamount of an acetylcholine esterase inhibitor.
 10. The method of claim9, wherein the acetylcholine esterase inhibitor is tacrine, donepezil,or rivastigmine.
 11. The method of claim 10, wherein the benzoic acid orthe pharmaceutically acceptable salt thereof is administered before,together with, or after the administration of the acetylcholine esteraseinhibitor.
 12. The method of claim 10, wherein the benzoic acid or thepharmaceutically acceptable salt thereof, and the acetylcholine esteraseinhibitor are formulated in a single formulation.
 13. The method ofclaim 9, wherein the subject is administered with a pharmaceuticalacceptable salt of benzoic acid, which is sodium benzoate, potassiumbenzoate, calcium benzoate, or lithium benzoate.
 14. The method of claim9, wherein the subject is administered with sodium benzoate.
 15. Themethod of claim 9, wherein the subject is administered with the benzoicacid or the pharmaceutically acceptable salt thereof at an amount of 300mg to 2000 mg per day.
 16. The method of claim 9, wherein the subject isadministered with the benzoic acid or the pharmaceutically acceptablesalt thereof at an amount of 500 mg to 2000 mg per day.
 17. The methodof claim 9, wherein the subject is administered with the benzoic acid orthe pharmaceutically acceptable salt thereof orally.